Phosphonic acid derivatives having carboxypeptidase b inhibitory activity

ABSTRACT

A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof:                    
     wherein R 1  represents hydrogen atom, an alkyl group, a substituted alkyl group and the like; R 2  and R 3  represent hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group and the like; X represents —CH 2 —, —O—, or —NH—; A represents the following group (II):                    
     [in which R 7  and R 8  represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group and the like; R 9  and R 10  represents hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group and the like] and the like; and E represents hydrogen atom and the like, which has inhibitory activity against carboxypeptidase B and is useful for therapeutic and/or preventive treatment of a thrombotic disease.

TECHNICAL FIELD

The present invention relates to phosphonic acid derivatives havinginhibitory activity against carboxypeptidase B, and to pharmaceuticalcompositions which comprise at least one of said derivative as an activeingredient and are useful for therapeutic and preventive treatment ofvarious thrombosis, diseases caused by a vascular disorder, and organdisorders resulting from reduction of fibrinolysis.

BACKGROUND ART

Numbers of patients suffering from circulatory diseases have beenincreasing due to growth of aged population and changes in socialcircumstances. Among the aforementioned diseases, those caused bythrombus such as cerebral infarction and myocardial infarction show anincreasing tendency. For these diseases, various antithrombotictreatments have been clinically applied.

The antithrombotic treatments are classified basically intoanticoagulant, antiplatelet, and thrombolytic treatments. Among them,the thrombolytic treatments involve the lysis of formed thrombus, perse. In that sense, they are considered as more reasonable remedies fortherapeutic treatment of thrombosis than the anticoagulant treatmentswhich prevent generation and development of secondary thrombus. Atpresent, enzymatic agents such as urokinase and plasminogen activatorhave been clinically used as thrombolytic agents, and their clinicaleffectiveness has been recognized as one of therapeutic treatments forpatients suffering from thrombosis.

Detailed mechanisms as to fibrinolysis have been being revealed with theprogress of biochemical researches. A factor, which was reported as afibrinogenolysis-inhibitory factor TAFI (thrombin activatablefibrinolysis inhibitor factor) activated by stimulation of coagulation,was revealed to be identical to plasma carboxypeptidase B (J. Biol.Chem., 14477(1995)). It was elucidated that plasma carboxypeptidase Binhibits fibrinolysis by interrupting plasminogen, which is afibrinolytic enzyme mainly acting in the lysis of thrombus (fibrin),from binding to thrombi (J. Clin. Invest., 2534(1995)., J. Biol. Chem.,16603(1996), Thromb. Haemost., 829(1998), Circulation, 1328(1996)).Accordingly, plasma carboxypeptidase B inhibitors are expected to beused as agents for therapeutic and preventive treatments of variousthromboses, which are antithrombotic agents based on enhancement of thelysis of thrombi.

As substances inhibiting pancreatic carboxypeptidase B, GEMSA(Biochemistry, 401(1978), Arch. Biochem. Biophys., 487(1979)), SQ24798(Biochemistry, 1427(1979)) and the like have been known so far.

Plasminogen activators and the like, which have been clinically used asthrombolytic agents at present, are not fully satisfactory from aclinical therapeutic viewpoint as their low safety such as hemorrhagicadverse effects and poor pharmacokinetics such as a short-half-life,although their thrombolytic activities in an acute stage after thrombusformation are reliable.

DISCLOSURE OF THE INVENTION

In order to provide a thrombolytic agent having higher safety, theinventors of the present invention conducted researches to find acompound having inhibitory activity against plasma carboxypeptidase B.As a result, they found that phosphonic acid derivatives have potentinhibitory activity against carboxypeptidase B.

The present invention thus provide a compound represented by thefollowing general formula (I) or a pharmacologically acceptable saltthereof, or a hydrate thereof or a solvate thereof:

wherein

R¹ represents hydrogen atom, an alkyl group, a substituted alkyl group,an alkoxyl group, a substituted alkoxyl group, amino group, asubstituted amino group, a carbocyclic group, a substituted carbocyclicgroup, a heterocyclic group, or a substituted heterocyclic group;

R² and R³ may be the same or different and independently representhydrogen atom, an alkyl group, a substituted alkyl group, an alkoxylgroup, a substituted alkoxyl group, amino group, a substituted aminogroup, a carbocyclic group, a substituted carbocyclic group, aheterocyclic group, or a substituted heterocyclic group, or R² and R³may form a 5 to 7 membered carbon ring together with the carbon atom towhich they bind;

X represents —CH₂—, —O—, or —NH—;

A represents a group of the following formula (II):

 [in which

R⁷ and R⁸ may be the same or different and independently representhydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group,an aryloxycarbonyl group, carbamoyl group, a substituted carbamoylgroup, or amidino group;

R⁹ and R¹⁰ may be the same or different and independently representhydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkylgroup, an alkoxyl group, an aryloxy group, an acyl group, carboxylgroup, an alkoxycarbonyl group, carbamoyl group, a substituted carbamoylgroup, amino group, a substituted amino group, nitro group, —SR¹¹ group(R¹¹ represents an alkyl group, phenyl group, or a substituted phenylgroup), —SOR¹² group (R¹² represents an alkyl group, phenyl group, asubstituted phenyl group, an alkoxyl group, an aryloxy group, aminogroup, or a substituted amino group), or —SO₂R¹³ group (R¹³ representsan alkyl group, phenyl group, a substituted phenyl group, an alkoxylgroup, an aryloxy group, amino group, or a substituted amino group);

m represents an integer of from 1 to 8; and

—(C)_(m)— represents a saturated or unsaturated carbon chain], or

A represents a group of the following formula (III):

 [in which

R⁷ and R⁸ may be the same or different and independently representhydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group,an aryloxycarbonyl group, carbamoyl group, a substituted carbamoylgroup, or amidino group;

R²⁴, R²⁵, R²⁶ and R²⁷ may be the same or different and independentlyrepresent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group,amino group, or a substituted amino group;

p and q independently represent an integer of from 0 to 2;

—(C)_(p)— and —(C)_(q)— independently represent single bond, or asaturated or unsaturated carbon chain; and

B represents a carbocyclic group, a substituted carbocyclic group, aheterocyclic group, or a substituted heterocyclic group], or

A represents a group of the following formula (IV):

 [in which

R²⁰ represents hydrogen atom, an alkyl group, an acyl group, analkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group, oramidino group; R²⁸ and R²⁹ may be the same or different andindependently represent hydrogen atom, a halogen atom, hydroxyl group,an alkyl group, amino group, or an alkylamino group;

n and o independently represent an integer of from 0 to 5;

r represents an integer of from 0 to 4;

—(C)_(r)— independently represents single bond, or a saturated orunsaturated carbon chain; and

Y represents CH or nitrogen atom], or

A represents a group of the following formula (XI):

 [in which

R⁷ and R⁸ may be the same or different and independently representhydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group,an aryloxycarbonyl group, carbamoyl group, a substituted carbamoylgroup, or amidino group;

R³⁰, R³¹, R³² and R³³ may be the same or different and independentlyrepresent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group,oxo group, amino group, or an alkylamino group;

s represents an integer of from 0 to 3;

t represents an integer of from 1 to 3;

—(C)_(s)— and —(C)_(t)— independently represent single bond, or asaturated or unsaturated carbon chain; and

V represents —O— or —NH—]; and,

E represents hydrogen atom, or —CH₂CH₂— to form together with A apiperidine ring group or a N-substituted piperidine ring group.

The present invention also provides a medicament which comprises as anactive ingredient a substance selected from the group consisting of thecompound represented by the aforementioned general formula (I) and apharmacologically acceptable salt thereof, and a hydrate thereof and asolvate thereof. According to a preferred embodiment, there is providedthe aforementioned medicament in the form of a pharmaceuticalcomposition which comprises the aforementioned substance as an activeingredient together with a pharmacologically acceptable carrier. Thesemedicaments are useful for therapeutic and/or preventive treatment ofthrombotic diseases.

The present invention also provides an inhibitor againstcarboxypeptidase B which comprises as an active ingredient the substanceselected from the group consisting of the compound represented by theaforementioned general formula (I) and a pharmacologically acceptablesalt thereof, and a hydrate thereof and a solvate thereof.

The present invention further provides a use of the substance selectedfrom the group consisting of the compound represented by theaforementioned general formula (I) and a pharmacologically acceptablesalt thereof, and a hydrate thereof and a solvate thereof for themanufacture of the aforementioned medicament; and a method fortherapeutic and/or preventive treatment of thrombotic diseases whichcomprises the step of administering to a mammal including a human atherapeutically and/or preventively effective amount of the substanceselected from the group consisting of the compound represented by theaforementioned general formula (I) and a pharmacologically acceptablesalt thereof, and a hydrate thereof and a solvate thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the specification, the alkyl group or an alkyl which constitutes apart of a substituent (e.g., alkoxyl groups) means a C₁₋₁₀ alkyl groupunless otherwise specifically mentioned, which encompasses straightchain alkyl groups including methyl group, ethyl group, n-propyl group,n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octylgroup and the like as typical examples; branched chain alkyl groups suchas isopropyl group, s-butyl group, t-butyl group, 2-pentyl group,3-pentyl group, and 1,1-dimethylpropyl group; cyclic alkyl groups suchas cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, and cycloheptyl group; and alkyl groups as combinations of astraight or branched chain alkyl group and a cyclic alkyl group, such ascyclopropylmethyl group, cyclopropylethyl group, and cyclobutylmethylgroup. In the groups containing an alkenyl moiety, the number of doublebonds contained in the alkenyl moiety is not particularly limited. Thealkenyl moiety may be any of a straight chain, a branched chain, cyclicmoiety, or a combination thereof unless otherwise specificallymentioned, and is preferably straight chain or branched chain. A doublebond contained in the alkenyl moiety may be in either Z- orE-configuration.

In the specification, the acyl group or an acyl group which constitutesa part of a substituent means a functional group selected from the groupconsisting of formyl group, straight chain or branched chain C₂₋₁₀alkylcarbonyl groups, C₇₋₁₅ aralkylcarbonyl groups, and C₄₋₇cycloalkycarbonyl groups. Examples include, for example, formyl group,acetyl group, propionyl group, butenyl group, benzoyl group, pivaloylgroup and the like, and is preferably acetyl group.

The halogen atom means fluorine atom, chlorine atom, bromine atom, oriodine atom, and preferably fluorine atom or chlorine atom.

In the specification, the aryl group or an aryl group which constitutesa part of a substituent means, unless otherwise specifically mentioned,a 6 to 14-membered (monocyclic to tricyclic, preferably monocyclic orbicyclic) aromatic ring group such as phenyl, 1-naphthyl, 2-naphthyl,biphenyl, and 2-anthrylnaphthyl.

A heteroring means a 5 to 14-membered, preferably 5 to 10-membered,(monocyclic to tricyclic, preferably monocyclic or bicyclic) heteroringwhich contains 1 to 4, preferably 1 to 3, heteroatoms of 1 or 2 kindsselected from oxygen atom, nitrogen atom, and sulfur atom other thancarbon atom. Examples include, for example, furan ring, pyrrole ring,pyrrolidine ring, pyrazole ring, imidazole ring, oxazole ring, thiazolering, triazole ring, pyrane ring, pyridine ring, piperidine ring,dioxane ring, morpholine ring, pyridazine ring, pyrimidine ring,pyrazine ring, piperazine ring, triazine ring and the like, andpreferably imidazole ring, triazole ring, pyridine ring, piperidinering, pyrimidine ring, pyrazine ring, piperazine ring and the like. Theheterocyclic group or a heterocyclic group which constitutes a part ofthe substituent means a residue of the aforementioned heteroring.

A carbon ring preferably means a saturated or unsaturated 5 to7-membered ring. Examples include, for example, cyclopropane ring,cyclobutane ring, cyclopentane ring, cyclopentyl ring, cyclohexane ring,cycloheptane ring, benzene ring and the like.

When m represents an integer of 2 or more, the description:

shows an alkylene group which consists of “m” groups of the methylenedefined in the parenthesis bound to each other in a chain, andrespective “m” groups of R⁹ and R¹⁰, each existing one to every “m”groups of the methylene, are independent and may be the same ordifferent. The aforementioned description should not be interpreted asmere repetition of “m” groups of the same methylene. The other alkylenegroups defined by p, q, r, s, or t are described in the same manner.

In formula (I), the alkyl group represented by R¹, R², or R³, or analkyl group existing on the substituent represented by R¹, R², or R³ ispreferably a C₁₋₈ alkyl group, more preferably a C₁₋₆ alkyl group, andfurther preferably a C₁₋₄ alkyl group. When the alkyl group representedby R¹, R², or R³ is a cyclic alkyl group, the group may preferably be aC₃₋₇ cycloalkyl group. Examples include, for example, cyclopropyl,cyclobutyl, cyclohexyl, cycloheptyl and the like.

One or more hydrogen atoms on the alkyl group represented by R¹, R², orR³ may be substituted. Examples of the substituent include hydroxylgroup, phenyl group, a substituted phenyl group, a halogen atom, analkoxyl group, a substituted alkoxyl group, an acyl group, carboxylgroup, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoylgroup, a substituted carbamoyl group, amino group, a substituted aminogroup, nitro group, oxo group, a carbocyclic group, a substitutedcarbocyclic group, a heterocyclic group, a substituted heterocyclicgroup, —SR⁴ group (R⁴ represents an alkyl group, phenyl group, or asubstituted phenyl group (examples of the substituent include a C₁₋₄alkyl group, a C₁₋₄ alkoxyl groups and the like)), —SOR⁵ groups (R⁵represents an alkyl group, phenyl group, a substituted phenyl group(examples of the substituent include a C₁₋₄ alkyl group, a C₁₋₄ alkoxylgroup and the like), an alkoxyl group, amino group, or an alkylaminogroup), —SO₂R⁶ group (R⁶ represents an alkyl group, phenyl group, asubstituted phenyl group (examples of the substituent include a C₁₋₄alkyl group, a C₁₋₄ alkoxyl group and the like), an alkoxyl group, aminogroup, or an alkylamino group) and the like. Preferred substituentsinclude hydroxyl group, phenyl group, a substituted phenyl group(substituted with hydroxyl group, a halogen atom, an alkoxyl group, anamino group), a halogen atom, an alkoxyl group, an acyl group (e.g.,acetyl group), carboxyl group, amino group, oxo group, and aheterocyclic group. The position of the substituent on the alkyl groupis not particularly limited. When 2 or more substituents exist on thealkyl group, they may be the same or different.

In formula (I), the alkoxyl group represented by R¹, R², or R³, or analkoxyl group existing on the substituent represented by R¹, R², or R³is preferably a C₁₋₈ alkoxyl group, more preferably a C₁₋₆ alkoxylgroup, and further preferably a C₁₋₅ alkoxyl group.

One or more hydrogen atoms on the alkoxyl group represented by R¹, R²,or R³ may be substituted. Examples of the substituent include hydroxylgroup, phenyl group, a substituted phenyl group, a halogen atom, analkoxyl group, a substituted alkoxyl group, an acyl group, carboxylgroup, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoylgroup, a substituted carbamoyl group, amino group, a substituted aminogroup, —SR²¹ group (R²¹ represents an alkyl group, phenyl group, or asubstituted phenyl group (examples of the substituent include a C₁₋₄alkyl group, a C₁₋₄ alkoxyl group and the like)), —SOR²² group (R²²represents an alkyl group, phenyl group, a substituted phenyl group(examples of the substituent include a C₁₋₄ alkyl group, a C₁₋₄ alkoxylgroup and the like), an alkoxyl group, amino group, or an alkylaminogroup), —SO₂R²³ group (R²³ represents an alkyl group, phenyl group, asubstituted phenyl group (examples of the substituent include a C₁₋₄alkyl group, a C₁₋₄ alkoxyl group and the like), an alkoxyl group, aminogroup, or an alkylamino group) and the like. A preferred substituentincludes phenyl group. The position of the substituent on the alkoxylgroup is not particularly limited. When 2 or more substituents exist onthe alkoxyl group, they may be the same or different.

In formula (I), one or two hydrogen atoms of the amino group representedby R¹, R², or R³ may be substituted. When two hydrogen atoms aresubstituted, the substituents may be the same or different. Examples ofthe substituent include an alkyl group, an alkenyl group, an acyl group,an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkylgroup, an arylalkyloxycarbonyl group, an alkylsulfonyl group, analkylsulfonylalkyl group, an arylsulfonyl groups, an arylsulfonylalkylgroup and the like. Examples of the substituted amino group includemethylamino group, ethylamino group, n-propylamino group, isopropylaminogroup, allylamino group, phenylamino group, benzylamino group,cyclohexylamino group, dimethylamino group, allylmethylamino group,allylcyclohexylamino group, formylamino group, acetylamino group,benzoylamino group, pivaloylamino group, acetylmethylamino group,phthaloylamino group, methoxycarbonylamino group,isopropoxycarbonylamino group, methoxycarbonylmethylamino group,benzyloxycarbonylamino group, methylsulfonylamino group,phenylsulfonylamino group, benzenesulfonylamino group, andmethyl(methylsulfonyl)amino group. Methylamino group, allylamino group,acetylamino group, methylsulfonylamino group, dimethylamino group,allylmethylamino group, or benzoylamino group is preferred.

In formula (I), the carbon ring represented by R¹, R², or R³, or thecarbon ring represented by R² and R³ together with the carbon atom towhich they bind may be substituted with a halogen atom, an alkyl group,an alkoxyl group, oxo group, an acyl group, carbamoyl group, aminogroup, or a substituted amino group. A specific example includes1-(3,5-dioxo)cyclohexyl group.

In formula (I), the heteroring represented by R¹, R², or R³ may besubstituted with an alkyl group, an alkoxyl groups, oxo group, an acylgroup, carbamoyl group, amino group, or a substituted amino group.

In formula (I), the group or atom represented by X is preferably oxygenatom.

In group (II), group (III), and group (XIV) represented by A in formula(I),examples of the group represented by R⁷ or R⁸ include hydrogen atom,an alkyl group, an acyl group, an alkoxycarbonyl group (e.g.,methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group,t-butoxycarbonyl group and the like), an aryloxycarbonyl group (e.g.,phenoxycarbonyl group and the like), carbamoyl group, an alkylcarbamoylgroup (e.g., methylcarbamoyl group, ethylcarbamoyl group,N,N-dimethylcarbamoyl group, N,N′-diethylcarbamoyl group and the like),an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like),and amidino group. Hydrogen atom, methyl group, ethyl group, formylgroup, or amidino group is preferred, and hydrogen atom or methyl groupis more preferred.

In group (II) represented by A in formula (I), examples of the grouprepresented by R⁹ or R¹⁰ include hydrogen atom, a halogen atom, hydroxylgroup, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group(e.g., phenoxy group and the like), an acyl group, carboxyl group, analkoxycarbonyl group (e.g., methoxycarbonyl group, isopropoxycarbonylgroup and the like), carbamoyl group, an alkylcarbamoyl group (e.g.,methylcarbamoyl group, N,N-dimethylcarbamoyl group, and the like), analkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), aminogroup, an alkylamino groups (e.g., methylamino group, ethylamino group,dimethylamino group and the like), an alkenylamino group (e.g.,allylmethylamino group and the like), an acylamino group (e.g.,acetylamino group, formylamino group, benzoylamino group and the like),an acylalkylamino group (e.g., acetylmethylamino group and the like), analkoxycarbonylamino group (e.g., methoxycarbonylamino group and thelike), nitro group, —SR¹¹ group {R¹¹ represents an alkyl group, phenylgroup or a substituted phenyl group (examples of the substituent includeC₁₋₄ alkyl groups, C₁₋₄ alkoxyl groups and the like)}, —SOR¹² group {R¹²represents an alkyl group, phenyl group, a substituted phenyl group(examples of the substituent include C₁₋₄ alkyl groups, C₁₋₄ alkoxylgroups and the like), an alkoxyl group (e.g., methoxy group, n-propoxygroup and the like), an aryloxy group (e.g., phenoxy group and thelike), amino group, or an alkylamino group (e.g., methylamino group,dimethylamino group and the like)}, and —SO₂R¹³ group {R¹³ represents analkyl group, phenyl group, a substituted phenyl group (examples of thesubstituent include a C₁₋₄ alkyl group, a C₁₋₄ alkoxyl group and thelike), an alkoxyl group (e.g., methoxy group, n-propoxy group and thelike), an aryloxy group (e.g., phenoxy group and the like), amino group,or an alkylamino group (e.g., methylamino group, dimethylamino group andthe like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group,ethyl group, or acetyl group is preferred, and hydrogen atom is morepreferred.

In group (II) represented by A in formula (I), the integer representedby m is preferably from 2 to 6, and more preferably 4 or 5.

In group (III) represented by A in formula (I), examples of the grouprepresented by R²⁴, R²⁵, R²⁶, or R²⁷ include hydrogen atom, a halogenatom, hydroxyl group, an alkyl group, amino group, and a substitutedamino group (examples of the substituent include C₁₋₄ alkyl groups andthe like).

In group (III) represented by A in formula (I), the carbon ringrepresented by B is preferably cyclohexane ring or benzene ring. One ormore hydrogen atoms on the carbon ring represented by B may besubstituted. Examples of the substituent include hydroxyl group, ahalogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxygroup (e.g., phenoxy group and the like), an acyl group (e.g., formylgroup, acetyl group, benzoyl group and the like), carboxyl group, analkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g.,methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), analkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), aminogroup, an alkylamino group (e.g., methylamino group, ethylamino group,dimethylamino group and the like), an alkenylamino group (e.g.,allylmethylamino group and the like), an acylamino group (e.g.,acetylamino group, formylamino group, benzoylamino group and the like),an acylalkylamino group (e.g., acetylmethylamino group and the like), analkoxycarbonylamino group (e.g., methoxycarbonylamino group and thelike), nitro group, —SR¹⁴ group {R¹⁴ represents an alkyl group, phenylgroup, or a substituted phenyl group (examples of the substituentinclude a C₁₋₄ alkyl group, a C₁₋₄ alkoxyl group and the like)}, —SOR¹⁵group {R¹⁵ represents an alkyl group, phenyl group, or a substitutedphenyl group (examples of the substituent include a C₁₋₄ alkyl group, aC₁₋₄ alkoxyl group and the like), an alkoxyl group, amino group, or analkylamino group (e.g., methylamino group, dimethylamino group and thelike)} and —SO₂R¹⁶ group {R¹⁶ represents an alkyl group, phenyl group,or a substituted phenyl group (examples of the substituent include aC₁₋₄ alkyl group, a C₁₋₄ alkoxyl group and the like), an alkoxyl group,amino group, or an alkylamino group (e.g., methylamino group,dimethylamino group and the like)}. Hydrogen atom, fluorine atom,chlorine atom, methyl group, ethyl group, acetyl group, carbamoyl group,carboxyl group, or nitro group is preferred.

In group (III) represented by A in formula (I), the heteroringrepresented by B is preferably imidazole ring, triazole ring, pyridinering, piperidine ring, pyrimidine ring, pyrazine ring, or piperazinering. One or more hydrogen atoms on the heteroring represented by B maybe substituted. Examples of the substituent include hydroxyl group, ahalogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxygroup (e.g., phenoxy group and the like), an acyl group (e.g., formylgroup, acetyl group, benzoyl group and the like), carboxyl group, analkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g.,methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), analkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), aminogroup, an alkylamino group (e.g., methylamino group, ethylamino group,dimethylamino group and, the like), an acylamino group (e.g.,acetylamino group, formylamino group, benzoylamino group and the like),an acylalkylamino group (e.g., acetylmethylamino group and the like), analkoxycarbonylamino group (e.g., methoxycarbonylamino group and thelike), nitro group, —SR¹⁷ group {R¹⁷ represents an alkyl group, phenylgroup, or a substituted phenyl group (examples of the substituentinclude a C₁₋₄ alkyl group, a C₁₋₄ alkoxyl group and the like)}, —SOR¹⁸group {R¹⁸ represents an alkyl group, phenyl group, a substituted phenylgroup (examples of the substituent include a C₁₋₄ alkyl group, a C₁₋₄alkoxyl group and the like.), an alkoxyl group, amino group, or analkylamino group (e.g., methylamino group, dimethylamino group and thelike)}, and —SO₂R¹⁹ group {R¹⁹ represents an alkyl group, phenyl group,a substituted phenyl group (examples of the substituent include a C₁₋₄alkyl group, a C₁₋₄ alkoxyl group and the like), an alkoxyl group, aminogroup, or an alkylamino group (e.g., methylamino group, dimethylaminogroup and the like)}. Hydrogen atom, fluorine atom, chlorine atom,methyl group, ethyl group, acetyl group, carbamoyl group, carboxylgroup, or nitro group is preferred.

In group (IV) represented by A in formula (I), examples of the grouprepresented by R²⁰ include hydrogen atom, alkyl groups, acyl groups,alkoxycarbonyl groups, carbamoyl group, alkylcarbamoyl groups (e.g.,methylcarbamoyl group and the like), and amidino group. Hydrogen atom oramidino group is preferred.

In group (IV) represented by A in formula (I), examples of the grouprepresented by R²⁸ or R²⁹ include hydrogen atom, halogen atoms, hydroxylgroup, alkyl groups, amino group, and alkylamino groups. Hydrogen atomis preferred.

In group (IV) represented by A in formula (I), the group or atomrepresented by Y is preferably CH.

In group (IV) represented by A in formula (I), the integer representedby n or o is preferably 2.

In group (IV) represented by A in formula (I), the integer representedby r is preferably 2.

In group (XIV) represented by A in formula (I), examples of the grouprepresented by R³⁰, R³¹, R³², or R³³ include hydrogen atom, halogenatoms, hydroxyl group, alkyl groups, amino group, oxo group, alkylaminogroups and the like. Hydrogen atom, an alkyl group, or oxo group ispreferred.

In group (XIV) represented by A in formula (I), the group or atomrepresented by V is preferably —O—.

In group (XIV) represented by A in formula (I), the integer representedby s or t is preferably 1 or 2.

In formula (I), examples of the N-substituent of the piperidine ringrepresented by E together with A include hydrogen atom, an alkyl group,a substituted alkyl group (examples of the substituent include hydroxylgroup, a halogen atom, amino group, an alkylamino group, an acylaminogroup, an alkoxycarbonylamino group, carbamoylamino group, guanidinogroup, oxo group, amidino group and the like), an acyl group, andamidino group. Hydrogen atom, an aminoalkyl group, an aminoalkyl grouphaving oxo group, or amidino group is preferred.

In formula (I), examples of the substituent of the substituted phenylgroup, which may substitute on the alkyl group or the alkoxyl grouprepresented by R¹, R² or R³, include hydroxyl group, a halogen atom,phenyl group, an alkyl group (e.g., a C₁₋₄ alkyl group and the like), analkoxyl group (e.g., a C₁₋₄ alkoxyl group and the like), an acyl group(e.g., formyl group, acetyl group, propionyl group, butenyl group,benzoyl group, pivaloyl group and the like), carboxyl group, analkoxycarbonyl group (e.g., a C₁₋₄ alkoxycarbonyl group and the like),an arylalkyloxycarbonyl group (e.g., benzyloxycarbonyl group and thelike), an aryloxycarbonyl group (phenoxycarbonyl group and the like),amino group, an alkylamino group (e.g., a C₁₋₄ alkylamino group,dimethylamino group, cyclohexylamino group and the like), analkenylamino group (e.g., allylamino group, allylmethylamino group,allylcyclohexylamino group and the like), an arylamino group (e.g.,phenylamino group and the like), an arylalkylamino group (e.g.,benzylamino group and the like), an acylamino group (e.g., formylaminogroup, acetylamino group, benzoylamino group, pivaloylamino group andthe like), an acylalkylamino group (e.g., acetylmethylamino group,phthaloylamino group and the like), an alkoxycarbonylamino group (e.g.,methoxycarbonylamino group, isopropoxycarbonylamino group and the like),an aryloxycarbonylamino group (e.g., benzyloxycarbonylamino group andthe like), an alkoxycarbonylalkylamino group (e.g.,methoxycarbonylmethylamino group and the like), an alkylsulfonylaminogroup (e.g., methylsulfonylamino group, methyl(methylsulfonyl)aminogroup and the like), an alkylsulfonylalkylamino group, anarylsulfonylamino group (e.g., benzenesulfonylamino group and the like),an arylsulfonylalkylamino group, carbamoyl group, an alkylcarbamoylgroup (e.g., methylcarbamoyl group, ethylcarbamoyl group,N,N-dimethylcarbamoyl group, N,N′-dimethylcarbamoyl group and the like),an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like),and nitro group. Hydroxyl group, a halogen atom, an alkoxyl group, oramino group is preferred.

In formula (I), an example of the substituent of the substituted alkoxylgroup, which may substitute on the alkyl group or alkoxyl grouprepresented by R¹, R², or R³, includes a C₁₋₄ alkoxyl group. Methoxygroup or isopropoxy group is preferred.

In formula (I), examples of the alkoxycarbonyl group or aryloxycarbonylgroup, which may substitute on the alkyl group or the alkoxyl grouprepresented by R¹, R², or R³, include a C₂₋₅ alkoxycarbonyl group,benzyloxycarbonyl group, and phenoxycarbonyl group. Methoxycarbonylgroup or isopropoxycarbonyl group is preferred.

In formula (I), examples of the substituted carbamoyl group, which maysubstitute on the alkyl group or the alkoxyl group represented by R¹,R², or R³, include a N-(C₁₋₄ alkyl)carbamoyl group, a N,N-di(C₁₋₄alkyl)carbamoyl group, and a N,N′-di(C₁₋₄ alkyl)carbamoyl group.Methylcarbamoyl group or N,N-dimethylcarbamoyl group is preferred.

In formula (I), examples of the substituted amino group, which maysubstitute on the alkyl group or the alkoxyl group represented by R¹,R², or R³, include an alkylamino group (e.g., methylamino group,ethylamino group, n-propylamino group, isopropylamino group,cyclohexylamino group, dimethylamino group and the like), analkenylamino group (e.g., allylamino group, allylmethylamino group,allylcyclohexylamino group and the like), an arylamino group (e.g.,phenylamino group and the like), an arylalkylamino group (e.g.,benzylamino group and the like), an acylamino group (e.g., formylaminogroup, acetylamino group, benzoylamino group, pivaloylamino group,phthaloylamino group and the like), an acylalkylamino group (e.g.,acetylmethylamino group and the like), an alkoxycarbonylamino group(e.g., methoxycarbonylamino group, isopropoxycarbonylamino group and thelike), an alkoxycarbonylalkylamino group (e.g.,methoxycarbonylmethylamino group and the like), an arylalkyloxycarbonylgroup (e.g., benzyloxycarbonylamino group and the like), analkylsulfonylamino group (e.g., methylsulfonylamino group,methyl(methylsulfonyl)amino group and the like), analkylsulfonylalkylamino group, an arylsulfonylamino group (e.g.,phenylsulfonylamino group and the like), and an arylsulfonylalkylaminogroup. Methylamino group, allylamino group, acetylamino group, ormethylsulfonylamino group is preferred.

Among the compounds represented by general formula (I), preferredcompounds include those wherein X is —O—.

Other preferred compounds include those wherein A is group (II).

Other preferred compounds also include those wherein E is —CH₂CH₂— thatforms piperidine ring group or a N-substituted piperidine ring grouptogether with A.

More preferred compounds are those wherein R¹ is an alkyl group, asubstituted alkyl group, an alkoxyl group, a substituted alkoxyl group,phenyl group, a substituted phenyl group, or a heterocyclic group, R²and R³ may be the same or different and independently are hydrogen atom,an alkyl group, a substituted alkyl group, phenyl group, or aheterocyclic group, or R² and R³ form a 5 to 7-membered carbon ringtogether with the carbon atom to which they bind, X is —O—, A is group(II), and E is hydrogen atom, or E is —CH₂CH₂— that forms piperidinering group or a N-substituted piperidine ring group together with A.

Other class of more preferred compounds are those wherein R¹ is an alkylgroup, a substituted alkyl group, an alkoxyl group, a substitutedalkoxyl group, phenyl group, a substituted phenyl group, or aheterocyclic group; R² and R³ may be the same or different and areindependently hydrogen atom, an alkyl group, a substituted alkyl group,phenyl group, or a heterocyclic group, or R² and R³ form a 5 to7-membered carbon ring together with the carbon atom to which they bind;X is —CH₂—, —O—, or —NH—; A is

(a) group (II) in which R⁷ and R⁸ may be the same or different and areindependently hydrogen atom, carbamoyl group, or amidino group; R⁹ andR¹⁰ may be the same or different and are independently hydrogen atom oran alkyl group; m is an integer of from 1 to 8; and —(C)_(m)— is asaturated carbon chain;

(b) group (III) in which both R⁷ and R⁸ are hydrogen atom; R²⁴, R²⁵,R²⁶, and R²⁷ may be the same or different and are independently hydrogenatom or an alkyl group; p and q are independently an integer of from 0to 2; —(C)_(p)— and —(C)_(q)— are independently single bond or asaturated carbon chain; and B is a carbocyclic group;

(c) group (IV) in which R²⁰ is hydrogen atom; R²⁸ and R²⁹ may be thesame or different and are independently hydrogen atom or an alkyl group;n and o are independently an integer of from 0 to 5; r is independentlyan integer of from 0 to 4; —(C)_(r)— is independently single bond or asaturated carbon chain; and Y is CH; or

(d) group (XIV) in which both R⁷ and R⁸ are hydrogen atom; R³⁰, R³¹,R³², and R³³ may be the same or different and are independently hydrogenatom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t isan integer of 1 to 3; —(C)_(s)— and —(C)_(t)— are independently singlebond or a saturated carbon chain; and V is —O—; and E is hydrogen atom,or E is —CH₂CH₂— that forms piperidine ring group or a N-substitutedpiperidine ring group together with A.

Further preferred compounds include those wherein R¹ is an alkyl group,a substituted alkyl group, an alkoxyl group, a substituted alkoxylgroup, phenyl group, a substituted phenyl group, or a heterocyclicgroup; R² and R³ may be the same or different and are independentlyhydrogen atom, an alkyl group, a substituted alkyl group, phenyl group,or a heterocyclic group, or R² and R³ form a 5 to 7-membered carbon ringtogether with the carbon atom to which they bind; X is —O—; A is:

(a) group (II) in which R⁷ and R⁸ may be the same or different and areindependently hydrogen atom, carbamoyl group, or amidino group; R⁹ andR¹⁰ may be the same or different and are independently hydrogen atom oran alkyl group; m is an integer of from 1 to 8; and —(C)_(m)— is asaturated carbon chain; or

(b) group (XIV) in which both R⁷ and R⁸ are hydrogen atom; R³⁰, R³¹,R³², and R³³ may be the same or different and are independently hydrogenatom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t isan integer of from 1 to 3; —(C)_(s)— and —(C)_(t)— are independentlysingle bond or a saturated carbon chain; and V is —O—; and E is hydrogenatom, or E is —CH₂CH₂— that forms piperidine ring group or aN-substituted piperidine ring group together with A.

Still further preferred compounds include those wherein R¹ is an alkylgroup or a phenylalkyl group; R² and R³ may be the same or different andare independently an alkyl group; X is —O—; A is group (II) in which R⁷and R⁸ may be the same or different and are independently hydrogen atom,carbamoyl group, or amidino group; R⁹ and R¹⁰ may be the same ordifferent and are independently hydrogen atom or an alkyl group; m is aninteger of from 1 to 8; and —(C)_(m)— is a saturated carbon chain; and Eis hydrogen atom.

Preferred specific examples of the compound represented by generalformula (I) include, but not limited thereto:

(S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-ethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-(((3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((cyclopropyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-5-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-cyclohexyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-cyclobutyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-4-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid,

(S)-6-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-4-ureido-butanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclohexyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-5-ureido-pentanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-4-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid,

(S)-5-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid,

(S)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-(1S)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoicacid,

(S)-6-amino-2-((3,3-dimethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((4,4,4-trifluoro-1-(3-phenylpropanoylamino)buty)hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid,

(R)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid,

(S)-7-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)heptanoicacid,

2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)-4-(piperidin-4-yl)butanoicacid,

1-(trans-(4-aminomethylcyclohexyl))-1-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)aceticacid,

3-aminoacetoxy-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)propanoicacid,

8-amino-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)octanoicacid,

(S)-6-amino-2-((1-phenyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-phenylpropanoylamino)-1-(tetrahydropyran-4-yl)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-5-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)pentanoicacid,

(S)-6-amino-2-((2-hydroxy-1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-cycloheptyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(piperidin-4-yl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((4-amino-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(4-methylcyclohexyl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-(((1R)-((2S)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-(1R)-phenylacetylaminopropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-((2R)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-cyclopentylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-benzoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-(2-methoxyphenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(4-methoxyphenyl)acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-heptanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(2-amino-2-phenylacetylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-((pyridin-2-yl)acetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-(((1R)-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-dodecanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-2-((1-acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)-6-aminohexanoicacid,

(S)-6-amino-2-((1-(3-(4-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-(3-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(trifluoroacetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(3-phenyl-(2S)-(3-phenylpropanoylamino)propanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-((3R)-hydroxybutanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-methoxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(3,4,5-trimethoxybenzoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((1-(3-carboxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(pyridin-2-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

(S)-6-amino-2-((2-methyl-1-(morpholine-4-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid,

4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid,

1-amidino-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid,

1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid,

(R)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid, and

7-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylheptanoicacid.

The compound represented by the aforementioned formula (I) mayoptionally have one or more asymmetric carbon atoms and exist as astereoisomer (an optical isomer or a diastereoisomer) based on theasymmetric carbon atom(s). Any mixtures of the stereoisomers andracemates as well as the stereoisomers in a pure form fall within thescope of the present invention, and any of the aforementioned substancesmay be used as an active ingredient of the medicament of the presentinvention. When the compound represented by the aforementioned formula(I) has an olefinic double bond, the compound may exist as a geometricalisomer in either Z- or E-form or a mixture thereof, any of which fallswithin the scope of the present invention. The geometrical isomer in apure form or a mixture thereof may be used as an active ingredient ofthe medicament of the present invention.

Among the compounds of formula (I) according to the present invention,those wherein X is oxygen atom or —NH— in formula (I) can be prepared bysynthetic method (I), (II), or (III) shown below. The compounds whereinX is —CH₂— and E is hydrogen atom can be prepared by the followingsynthetic method (IV), (V), (VI), or (VII). The compounds wherein X is—CH₂— and E is —CH₂CH₂— that forms a piperidine ring group or aN-substituted piperidine ring group together with A can be prepared bysynthetic method (VI) or (VII). However, preparations of the compoundsof the present invention are not limited to these methods.

In order to synthesize the compound of formula (I) of the presentinvention, the amino group (the amino group herein defined includes anamino group on the piperidine ring formed by E together with A.), iminogroup, and carboxyl group used in the following synthetic methods (I) to(VII) may be protected, if desired. As a protecting group, ordinaryprotecting groups can be used. Preferably, examples for an amino group.or an imino group includes methoxycarbonyl group, tert-butyloxycarbonylgroup, benzyloxycarbonyl group, methoxybenzyloxycarbonyl group,nitrobenzyloxycarbonyl group, allylbenzyloxycarbonyl group, acetylgroup, trifluoroacetyl group, trichloroacetyl group, benzoyl group,phthaloyl group, trityl group, benzyl group, methoxybenzyl group, allylgroup, formyl group and the like, and examples for carboxyl groupinclude methyl group, tert-butyl group, benzyl group, paramethoxybenzylgroup, nitrobenzyl group, allyl group, benzhydryl group, trityl groupand the like.

[In the scheme, R¹, R², R³, A, and E have the same meanings as thosedefined in formula (I), W represents oxygen atom or —NH—, and Zrepresents hydrogen atom, hydroxyl group, or alkoxyl group.]

A compound of the formula (VII) can be prepared according to the methoddescribed in Tetrahedron Lett., 7333 (1991), U.S. Pat. No. 4,616,005 orthe like. Specifically, the method comprises condensing a compound offormula (V) and a compound of formula (VI) by applying, for example, thedehydration method using N,N′-dicyclohexylcarbodiimide (DCC),benzotriazoleoxytrisdimethylamino-phosphonium tetrafluorophosphate (BOP)or the like, the acid halide method using thionyl chloride, oxalylchloride, phosphorus oxychloride or the like, the mixed acid anhydridemethod using pivaloyl chloride, a chloroformic acid ester or the like ina solvent which does not participate in the reaction for a reaction timeof from 0.5 to 72 hours, preferably from 2 to 24 hours at a reactiontemperature of from −78° C. to 100° C., preferably from 0° C. to 30° C.

As the amine of formula (VI), a commercially available compound maybeused, or the amine can be synthesized according to the method describedin Synthesis, 370(1988), Liebigs. Ann. Chem., 861(1988), J. Chem. Soc.Perkin trans. 1,2846(1984) or the like. Where Z is hydrogen atom in thecompound of formula (VII), the hydrogen atom can be converted intohydroxyl group by an ordinary oxidation in this step, and the hydroxylgroup may be converted into an alkoxyl group, if desired.

The condensation between the compound of formula (VII) and a carboxylicacid compound of formula (VIII) can be carried out according to themethod described in J. Am. Clem. Soc., 297(1991), J. Org. Chem.,658(1994), J. Med. Chem., 3303(1998), Synthesis, 556(1986), J. Med.Chem., 1459(1990), Tetrahedron Lett., 1751(1986) or the like.Specifically, the method comprises condensing the compound of formula(VII) and the compound of formula (VIII) by applying, for example, thedehydration method using N-(dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride, N,N′-dicyclohexylcarbodiimide (DCC),benzotriazoleoxytrisdimethylamino-phosphonium tetrafluorophosphate (BOP)or the like, the acid halide method using thionyl chloride, oxalylchloride, phosphorus oxychloride or the like, the mixed acid anhydridemethod using pivaloyl chloride, a chloroformic acid ester or the like ina solvent which does not participate in the reaction for a reaction timeof from 0.5 to 72 hours, preferably from 2 to 24 hours at a reactiontemperature of from −78° C. to 100° C., preferably from 0° C. to 30° C.The compound wherein X is oxygen atom or —NH— in formula (I) can besynthesized through deprotection at need after the condensation, or whenZ is hydrogen atom, by performing oxidation according to a conventionalmethod after the condensation, and then deprotection at need.

[In the scheme, R¹, R², R³, A, E, W, and Z have the same meanings asthose defined above.]

The compound of formula (I) can be synthesized according to the methodshown in the aforementioned synthetic method (I).

Where Z is hydrogen atom in a compound of formula (IX), the hydrogenatom can be converted into hydroxyl group by an ordinary oxidation inthis step, and the resulting hydroxyl group may be converted into analkoxyl group, if desired.

The condensation between the compound of formula (V) and the compound offormula (IX) can be performed in the same manner as those described inthe aforementioned synthetic method (I). The compound wherein X isoxygen atom or —NH— in formula (I) can be synthesized throughdeprotection at need after the condensation, or where Z is hydrogenatom, by an oxidation in a conventional manner after the condensation,and then deprotection at need.

[In the scheme, R¹, R², R³, A, E, W, and Z have the same meanings asthose defined above.]

A compound of formula (X) can be prepared according to the methoddescribed in Tetrahedron Lett., 5457(1996), Ibid., 6073(1996) or thelike. Specifically, the compound of formula (X) wherein Z is hydroxylgroup or an alkoxyl group can be obtained by reacting a compound offormula (VIII) with a phosphorylating agent such as2-chloro-4H-1,3,2-benzodioxaphophorin-4-one,2-chloro-1,3,2-dioxaphophorane, 2-cyanoethylN,N′-diisopropylchlorophosphoramidate, and phosphorus trichloride in asolvent which does not participate in the reaction for a reaction timeof from 0.5 to 72 hours, preferably from 2 to 24 hours, at a reactiontemperature of from −78° C. to 100° C., preferably from −30° C. to 30°C., and then performing hydrolysis or alcoholysis, if desired. When Z ishydroxyl group in formula (X), a compound wherein Z is an alkoxyl groupin formula (X) can also be obtained by performing esterification by aconventional method.

A compound of formula (IX) can be synthesized according to the methoddescribed in Tetrahedron Lett., 5457(1996) or the like. Specifically,the compound of formula (IX) wherein Z is hydroxyl group or an alkoxylgroup can be obtained by reacting the compound of formula (X) with thecompound of formula (XI), per se, or under irradiation by ultrasound orin the presence of a Lewis acid such as boron trifluoride, titaniumchloride, tin chloride and yttrium triflate, in a solvent which does notparticipate in the reaction for a reaction time of from 0.5 to 72 hours,preferably from 2 to 24 hours at a reaction temperature of from −78° C.to 100° C., preferably from −30° C. to 60° C., and then performingdeprotection at need. The compound of formula (I) can be synthesizedaccording to the method of synthetic method (I).

[In the scheme, R¹, R², R³, and A have the same meanings as thosedefined above, and Z represents hydrogen atom.]

A compound of formula (VII) can be synthesized by the method shown inthe aforementioned synthesis method (I).

The reaction of the compound of formula (VII) and a compound of formula(XII) can be carried out according to the method described in Bioorg.Med. Chem. Lett., 1257(1996), J. Med. Chem., 1652(1989), J. Am. Chem.Soc., 297(1991), Tetrahedron Lett., 3375(1998), Tetrahedron Lett.,2933(1990), or the like. Specifically, the method comprises activatingor esterifying the compound of formula (VII), if desired, by using asilyl group or the like to elevate the reactivity of the compound offormula (VII), and subjecting the compound of formula (XII) to Michaeladdition in a solvent which does not participate in the reaction orwithout solvent, for a reaction time of from 0.5 to 72 hours, preferablyfrom 2 to 24 hours at a reaction temperature of from −78° C. to 100° C.,preferably from 0° C. to 50° C. The compound wherein X is —CH₂— and E ishydrogen atom in formula (I) can be synthesized through deprotection atneed after the Michael addition.

A compound of formula (XII) can be synthesized according to the methoddescribed in J. Med. Chem., 2461(1994) or the like.

[In the scheme, R¹, R², R³, and A have the same meanings as thosedefined above, and Z represents hydrogen atom.]

A compound of formula (XIII) can be synthesized according to the methodshown in the aforementioned synthetic method (IV).

The condensation between the compound of formula (V) and the compound offormula (XIII) can be performed according to the method shown in theaforementioned synthetic method (I), and the compound wherein X is —CH₂—and E is hydrogen atom in formula (I) can be synthesized throughdeprotection at need after the condensation.

[In the scheme, R¹, R², R³, and A have the same meanings as thosedefined above, E represents hydrogen atom or —CH₂CH₂— that formspiperidine ring group or a N-substituted piperidine ring group togetherwith A, and Z represents hydrogen atom.]

The compound of formula (VII) can be synthesized by the method shown inthe aforementioned synthetic method (I).

A compound of formula (XVI) can be synthesized according to the methoddescribed in J. Med. Chem., 2461(1994) or the like.

The condensation between the compound of formula (VII) and the compoundof formula (XVI) can be performed according to the method described inBioorg. Med. Chem. Lett., 1629(1996). Specifically, the compound whereinX is carbon atom in formula (I) can be synthesized by activating thehydroxyl group in formula (XVI) with trifluoromethanesulfonic anhydride,methanesulfonyl chloride, toluenesulfonyl chloride or the like, orsubstituting the hydroxyl group in formula (XVI) with a halogen atom bya conventional method, and by activating or esterifying the compound offormula (VII) with silyl group or the like at need to elevate thereactivity of the compound of formula (VII), and then, carrying out thereaction in a solvent which does not participate in the reaction orwithout solvent, in the presence of base at need such as triethylamine,diisopropylethylamine, pyridine, lutidine, potassium carbonate, sodiumhydrogencarbonate, sodium hydride and lithium diisopropylamide, for areaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours ata reaction temperature of from −78° C. to 100° C., preferably from −78°C. to 60° C., and performing deprotection at need.

[In the scheme, R¹, R², R³, and A have the same meanings as thosedefined above, E represents hydrogen atom or —CH₂CH₂— that formspiperidine ring group or a N-substituted piperidine ring group togetherwith A, and Z represents hydrogen atom.]

A compound of formula (XVII) can be synthesized according to the methodshown in the aforementioned synthetic method (VI). The condensationbetween the compound of formula (V) and the compound of formula (XVII)can be performed according to the method shown in the aforementionedsynthetic method (I), and the compound wherein X is —CH₂— in formula (I)can be synthesized through deprotection after the condensation.

Specific preparations of the compound of the present inventionencompassed within formula (I) are shown in Examples of thespecification. Those of ordinary skill in the art can easily prepare thecompound of the present invention falling within formula (I) byreferring to the aforementioned general explanation and specificexplanation in examples, and by appropriately selecting a startingmaterial, a reagent, reaction conditions and the like, and if necessary,applying appropriate modifications and alterations to these methods.

The compound of formula (I) according to the present invention may existas a salt, and may preferably exist as a pharmacologically acceptablesalt. Such salts include medicinally acceptable nontoxic salts, forexample, alkali metal salts and alkaline-earth metal salts such assodium salt, potassium salt, and calcium salt, hydrogen halide saltssuch as hydrochloride, inorganic salts such as nitrate, sulfate andphosphate, salts of sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid, salts of organic acids such as fumaric acid,succinic acid, citric acid, oxalic acid and maleic acid, salts of aminoacids such as glutamic acid and aspartic acid, and the like.

The compound of formula (I) according to the present invention may existas a hydrate or a solvate. Preferred solvates include a solvate withethanol and the like. Any salts, hydrates, and solvates of the compoundof formula (I) fall within the scope of the present invention.

The compound of formula (I) according to the present invention havethrombolytic activity based on inhibition of carboxypeptidase B in humanplasma. Accordingly, a substance selected from the group consisting ofthe compound of formula (I) according to the present invention and apharmacologically acceptable salt thereof, and a hydrate thereof and asolvate thereof is useful as an active ingredient of medicaments fortherapeutic and/or preventive treatment of various thrombotic diseasessuch as myocardial infarction, cerebral infarction, angina, pulmonaryembolus, chronic arterial obliteration, acute arterial thrombus andembolus, angitis syndrome, diabetic gangrene, thrombophlebitis and deepvein thrombosis, thrombotic thrombocytopenic purpura andhemolytic-uremic syndrome, disseminated intravascular coagulation, andanti-phospholipid antibody syndrome, and pathologic conditions such asdiabetes, hyperlipemia, and inflammation in which thrombotic tendencydue to the decrease of in vivo fibrinoliablity have been recognized.

The substance selected from the group consisting of the compound offormula (I) according to the present invention and a pharmacologicallyacceptable salt thereof, and a hydrate thereof and a solvate thereof isalso effective as a carboxypeptidase B inhibitor. As thecarboxypeptidase B inhibitor according to the present invention, theaforementioned substance, per se, can be used. For example, theinhibitor can also be used as a reagent for enzymes.

The substance selected from the group consisting of the compound offormula (I) according to the present invention and a pharmacologicallyacceptable salt thereof, and a hydrate thereof and a solvate thereof,per se, may be used as a medicament. However, the medicament of thepresent invention is preferably provided as a pharmaceutical compositionwhich comprises the aforementioned substance together with apharmacologically acceptable carrier, and can be administered to a humanas well as an animal other than human by either an oral or parenteral(e.g., intravenous, intramuscular, subcutaneous, rectal, transdermal andthe like) administration. Two or more of the aforementioned substancesmay be formulated in combination in the pharmaceutical composition.

The pharmaceutical composition which comprises as an active ingredient asubstance selected from the group consisting of the compound of formula(I) according to the present invention and a pharmacologicallyacceptable salt thereof, and a hydrate thereof and a solvate thereof canbe prepared as a formulation suitable for a route of administration.Specifically, the pharmaceutical composition can be prepared typicallyin any one of formulations including preparations for parenteraladministration such as injections for intravenous or intramuscularadministration, drip infusions, inhalants, transdermal preparations,transmucosal preparations, rectal preparations, oleaginoussuppositories, and aqueous suppositories, and preparations for oraladministration such as capsules, tablets, granules, powders, pills, finegranules, and troches.

As the pharmacologically acceptable carrier used for the manufacture ofthese various preparations, one or more solid or liquid carrierssuitable for administration to humans as well as animals other thanhumans can be used. Examples of the solid carriers include, for example,starch, lactose, crystalline cellulose, calcium carbonate and the like.Examples of the liquid carriers include, for example, physiologicalsaline, ethanol and the like.

One or more kinds of commonly used excipients, bulking agents, binders,moisturizing agents, disintegrators, surface active agents, lubricants,dispersants, buffering agents, preservatives, solubilizing aids,antiseptics, corrigents, soothing agents, stabilizers and the like maybe used as the pharmacologically acceptable carrier. Examples of usablenontoxic carriers include, for example, lactose, fructose, glucose,starch, gelatin, magnesium carbonate, synthetic magnesium silicate,talc, magnesium stearate, methylcellulose and its salts, gum arabic,polyethylene glycol, syrup, Vaseline, ethanol, propylene glycol, citricacid, sodium chloride, sodium sulfite, sodium phosphate and the like.

The content of the substance selected from the group consisting of thecompound of formula (I) according to the present invention and apharmacologically acceptable salt thereof, and a hydrate thereof and asolvate thereof contained in the pharmaceutical composition may varydepending on dosage forms. Generally, the amount may be from about 1% toabout 70% by weight, preferably from about 5% to about 50% by weightbased on the total weight of the composition.

A dose can be appropriately chosen in view of the use of the medicament,the age, sexuality and conditions of a patient and the like. The dosemay generally be from about 0.1 mg to 1,000 mg, and preferably from 1 mgto 300 mg per day for an adult for therapeutic treatment of thromboticdiseases. The aforementioned dose can be administered once a day orseveral times a day as divided portions.

EXAMPLES

The present invention will be explained more specifically by examples.However, the scope of the present invention is not limited to thefollowing examples.

Example 1(S)-6-Amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) (R)-1-(benzyloxycarbonylamino)ethylphophonic acid monomethyl ester(40.7 mg) described in Biochemistry, 6294(1989) was dissolved intetrahydrofuran (1 ml), and pivaloyl chloride (71.8 mg) andtriethylamine (90.4 mg) were added. The mixture was stirred at roomtemperature for 30 minutes, then added with a tetrahydrofuran (1 ml)solution of methyl (S)-2-hydroxy-6-(tert-butoxycarbonylamino)hexanoate(38.9 mg), which is obtainable from 6-amino-2-hydroxyhexanoic aciddescribed in Chem. Pharm. Bull., 621(1976) by a conventional method, andstirred at room temperature overnight. The organic substances wereextracted with ethyl acetate and the extract was washed with saturatedbrine, and then the organic layer was dried over anhydrous sodiumsulfate. The residue was purified by silica gel thin-layerchromatography to obtain methyl(S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate(9.7 mg, 13%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction.

TSPMS(m/z): 517(M⁺+1).

(b) A methanol (1 ml) solution of the methyl(S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate(9.7 mg) obtained in the above step (a)was added with potassiumcarbonate (5.7 mg), and the mixture was stirred at room temperature for3 hours. The mixture was acidified with hydrochloric acid and theorganic substances were extracted with ethyl acetate. The extract waswashed with saturated brine, and then the organic layer was dried overanhydrous sodium sulfate to obtain(S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoicacid (3.1 mg, 34%). This compound was subjected to the measure m en t ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 489(M⁺+1).

(c) A dichloromethane (0.5 ml) suspension of the(S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoicacid (3.1 mg) obtained in the above step (b) was added with anisol (0.05ml) and trifluoroacetic acid (0.5 ml) at 0° C., and the mixture wasstirred at the same temperature for 2 hours. The reaction mixture wasconcentrated, and the residue was washed with isopropyl ether to obtaintrifluoroacetic acid salt of the title compound:(S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid (3.0 mg, 94%).

¹H-NMR(D₂O): δ1.1-1.8(9H,m), 2.8-2.9(2H,m), 3.5-3.7(1H,m),4.1-4.2(1H,m), 4.97(2H,s), 7.2-7.5(5H,m).

TSPMS(m/z): 389(M⁺+1).

Example 2(S)-6-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) 1-Amino-2-methylpropylphosphinic acid (99.8 mg) prepared by themethod described in J. Chem. Soc. Perkin tans 1, 2845(1984) wasdissolved in 5 N aqueous sodium hydroxide (0.3 ml). 3-Phenylpropanoylchloride (0.1 ml) was added to the solution at 0° C., and the resultingmixture was stirred at 0° C. for 1 hour and at room temperature for 3hours. The mixture was acidified with hydrochloric acid and added withsodium chloride, and then the organic substances were extracted withethyl acetate. The extract was washed with saturated aqueous sodiumchloride and then the organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated to obtain2-methyl-1-(3-phenylpropanoylamino)propylphosphinic acid (162 mg, 82%).This compound was subjected to the measurement of molecular weight andthen used in the following reaction without further purification.

TSPMS (m/z): 270(M⁺+1).

(b) Under an argon atmosphere, a dichloromethane (15 ml) solution of the2-methyl-1-(3-phenylpropanoylamino)propylphosphinic acid (162 mg)obtained in the above step (a) was added with benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate (228 mg) which wasobtained from 6-amino-2-hydroxyhexanoic acid described in Chem. Pharm.Bull., 621(1976) in a conventional manner,N-(dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (180 mg), anddimethylaminopyridine (38.7 mg), and then the mixture was stirred atroom temperature for 16 hours. The organic substances were extractedwith ethyl acetate, and the extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography (10 g,chloroform:methanol=10:1) to obtain benzyl(S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate(117 mg, 31%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction.

TSPMS(m/z): 623(M⁺+1).

(c) The benzyl(S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate(117 mg) obtained in the above step (b) was dissolved in a mixed solventof dioxane (4.5 ml) and water (1.5 ml) and added with sodium periodate(40.4 mg), and then the mixture was stirred at room temperature for 15hours. The organic substances were extracted with ethyl acetate, and theextract was washed with saturated aqueous sodium thiosulfate andsaturated brine, successively, and dried over anhydrous magnesiumsulfate. Then the solvent was evaporated to obtain benzyl(S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate(100.8 mg, 84%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 639(M⁺+1).

(d) The benzyl(S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate(85 mg) obtained in the above step (c) was dissolved in a mixed solventof dioxane (2.4 ml) and water (0.8 ml) and added with palladiumhydroxide (45.8 mg), and the mixture was stirred under a hydrogenatmosphere at room temperature for 24 hours. The reaction mixture wasfiltered with celite and the filtrate was concentrated. The residue waspurified with HP-20 (Diaion, 10 cc, methanol:water=1:4 to 1:1) to obtainthe title compound:(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (25 mg, 45%) (a diastereoisomeric mixture of 1:1).

¹H-NMR(D₂O): δ0.56(3/2H,d), 0.59(3H,m), 0.66(3/2H,d), 1.2-1.5(2H,m),1.6-1.8(4H,m), 1.8-2.0(1H,m), 2.5-2.7(2H,m), 2.8-3.0(4H,m),3.7-3.9(1H,m), 4.3-4.5(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ18.7(1/2P,s), 19.7(1/2P,s).

TSPMS(m/z): 415(M⁺+1).

Example 3(S)-6-Amino-2-((2-ethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((2-ethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-2-ethylbutylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.5-0.8(8H,m), 1.0-1.2(1H,m), 1.2-1.8(8H,m),2.4-2.7(2H,m), 2.7-3.0(4H,m), 3.9-4.1(1H,m), 4.3-4.5(1H,m),7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ19.5(1/2P,s), 20.6(1/2P,s).

TSPMS(m/z): 443(M⁺+1).

Example 4(S)-6-Amino-2-((1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-aminoethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.92(3/2H,dd), 0.95(3/2H,dd), 1.2-1.4(2H,m),1.5-1.8(4H,m), 2.3-2.5(2H,m), 2.7-3.0(4H,m), 3.7-4.0(1H,m),4.5-4.7(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ20.4(1/2P,s), 20.8(1/2P,s).

TSPMS(m/z): 387(M⁺+1).

Example 5(S)-6-Amino-2-(((3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-(((3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using aminomethylphosphinic acid as a startingmaterial.

¹H-NMR(D₂O): δ1.2-1.4(2H,m), 1.4-1.7(4H,m), 2.44(2H,t), 2.78(2H,t),2.85(2H,t), 3.1-3.3(2H,m), 4.3-4.4(1H,m), 7.1-7.3(5H,m).

TSPMS(m/z): δ373(M⁺+1).

Example 6(S)-6-Amino-2-((1-cyclopropyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-cyclopropyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-cyclopropylmethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ−0.1-0.2(2H,m), 0.2-0.4(1H,m), 0.4-0.6(1H,m),0.8-1.1(1H,m), 1.3-1.6(2H,m), 1.6-1.9(4H,m), 2.5-2.7(2H,m),2.8-3.1(4H,m), 3.45(0.5H,dd), 3.56(0.5H,dd), 4.4-4.6(1H,m),7.2-7.5(5H,m).

³¹P-NMR(D₂O): δ15.6(1/2P,s), 16.4(1/2P,s).

TSPMS(m/z): 413(M⁺+1).

Example 7(S)-5-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid

In the same manner as the method of Example 2, the title compound:(S)-5-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using benzyl(S)-5-benzyloxycarbonylamino-2-hydroxypentanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) of Example 2.

¹H-NMR(D₂O): δ0.50(3/2H,d), 0.52(3H,d), 0.58(3/2H,d), 1.4-1.7(4H,m),1.86(1H,m), 2.5(2H,m), 2.76-2.99(4H,m), 3.72(1H,dd), 4.37(1H,m),7.1-7.2(5H,m).

³¹P-NMR(D₂O): δ18.81(1/2P,s), 18.82(1/2P,s).

TSPMS(m/z): 401(M⁺+1).

Example 8(S)-6-Amino-2-((1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-aminobutylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.7-0.8(3H,m), 0.8-1.0(2H,m), 1.2-1.3(1H,m),1.3-1.9(7H,m), 2.6-2.7(2H,m), 2.9-3.1(4H,m), 3.9-4.0(1H,m),4.4-4.6(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ19.5(1/2P,s), 20.2(1/2P,s).

TSPMS(m/z): 415(M⁺+1).

Example 9(S)-6-Amino-2-((1-cyclohexyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((cyclohexyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-cyclohexylmethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.4-0.7(2H,m), 0.8-1.0(1H,m), 1.0-1.2(2H,m),1.3-1.8(12H,m), 2.6-2.8(2H,m), 2.9-3.1(4H,m), 3.8-3.9(1H,m),4.4-4.5(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ18.6(1/2P,s), 19.9(1/2P,s).

TSPMS(m/z): 455(M⁺+1).

Example 10(S)-6-Amino-2-((1-cyclobutyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-cyclobutyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using 1-amino-1-cyclobutylmethylphosphinic acid asa starting material.

¹H-NMR(D₂O): δ1.3-1.6(5H,m), 1.6-1.9(7H,m), 2.5-2.7(3H,m),2.9-3.1(4H,m), 3.8-4.0(1H,m), 4.6-4.7(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ18.5(1/2P,s), 19.1(1/2P,s).

TSPMS(m/z): 427(M⁺+1).

Example 11(S)-4-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid

In the same manner as the method of Example 2, the title compound:(S)-4-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using benzyl(S)-4-benzyloxycarbonylamino-2-hydroxybutanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) of Example 2.

¹H-NMR(D₂O): δ0.50(3/2H,d), 0.52(3H,d), 0.58(3/2H,d), 1.8-1.9(3H,m),2.5(2H,m), 2.8(2H,m), 2.9(2H,m), 3.79(1H,dd), 4.38(1H,m), 7.1-7.2(5H,m).

³¹P-NMR(D₂O): δ19.53(1/2P,s), 20.41(1/2P,s).

TSPMS(m/z): 387(M⁺+1).

Example 12(S)-6-Amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-3-methylbutylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.67(3H,d), 0.7-0.8(3H,m), 0.8-0.9(1H,m), 1.3-1.6(4H,m),1.6-1.8(2H,m), 1.8-1.9(2H,m), 2.5-2.6(2H,m), 2.8-3.0(4H,m),3.9-4.1(1H,m), 4.6-4.7(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ20.6(1/2P,s),20.9(1/2P,s).

TSPMS(m/z): 429(M⁺+1).

Example 13(S)-2-((2-Methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-4-ureido-butanoicacid

An aqueous solution (20 ml) of the(S)-4-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid (100 mg) obtained in Example 11 was added with potassium cyanate(84 mg) at room temperature and the mixture was stirred at 60° C. for 4hours. The solvent was evaporated, and the residue was purified withHP-20 (Diaion, water:methanol=10:1) to obtain potassium salt of thetitle compound:(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-4-ureido-butanoicacid (a diastereoisomeric mixture of 1:1) (95 mg).

¹H-NMR(D₂O): δ0.51(3/2H,d), 0.55(3H,d), 0.60(3/2H,d), 1.7-1.9(,3H,m),2.5(2H,m), 2.8(2H,m), 3.0(2H,m), 3.74(1H,dd), 4.36(1H,m), 7.1-7.2(5H,m).

TSPMS(m/z): 430(M⁺+1).

Example 14(S)-6-Amino-2-((1-(3-phenylpropanoylamino)cyclohexyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 20, the title compound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclohexyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using cyclohexanone as a starting material.

¹H-NMR(D₂O): δ0.7-0.9(2H,m), 1.0-1.1(1H,m), 1.4-1.6(7H,m),1.6-1.8(4H,m), 2.2-2.3(2H,m), 2.61(2H,t), 2.94(2H,t), 3.03(2H,t),4.4-4.5(1H,m), 7.2-7.4(5H,m).

TSPMS(m/z): 441(M⁺+1).

Example 15(S)-2-((2-Methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-5-ureido-pentanoicacid

In the same manner as the method of Example 13, potassium salt of thetitle compound:(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-5-ureido-pentanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using the(S)-5-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid obtained in Example 7 as a starting material.

¹H-NMR(D₂O): δ0.56(3/2H,d), 0.59(3H,d), 0.64(3/2H,d), 1.4(2H,m),1.65(2H,brs), 1.92(1H,m), 2.59(2H,m), 2.85(2H,m), 3.00(2H,m),3.77(1H,dd), 4.39(1H,m), 7.1-7.3(5H,m).

TSPMS(m/z): δ444(M⁺+1).

Example 16(S)-6-Amino-2-((1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, sodium salt of the titlecompound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-aminopropylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.5-0.7(3H,m), 1.2-1.9(8H,m), 2.5-2.7(2H,m),2.8-3.0(4H,m), 3.7-3.9(1H,m), 4.5-4.6(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ19.2(1/2P,s), 19.9(1/2P,s).

TSPMS(m/z): 401(M⁺+1).

Example 17(S)-4-Guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid

In the same manner as the method of Example 2, the title compound:(S)-4-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using benzyl(S)-4-(2,3-bis(benzyloxycarbonyl)guanidino)-2-hydroxybutanoate insteadof benzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) ofExample 2.

¹H-NMR(D₂O): δ0.55(3/2H,d), 0.58(3H,d), 0.63(3/2H,d), 1.8-1.9(3H,m),2.55(2H,m), 2.82(2H,m), 3.15(2H,m), 3.79(1H,dd), 4.39(1H,m),7.1-7.2(5H,m).

³¹P-NMR(D₂O): δ19.12(1/2P,s), 20.10(1/2P,s).

TSPMS(m/z): 429(M⁺+1).

Example 18(S)-5-Guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid

In the same manner as the method of Example 2, the title compound:(S)-5-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using benzyl(S)-5-(2,3-bis(benzyloxycarbonyl)guanidino)-2-hydroxypentanoate insteadof benzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) ofExample 2.

¹H-NMR(D₂O): δ0.52(3/2H,d), 0.56(3H,d), 0.61(3/2H,d), 1.5(2H,m),1.65(2H,brs), 1.88(1H,m), 2.56(2H,m), 2.83(2H,m), 3.07(2H,m),3.74(1H,dd), 4.37(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ18.77(1/2P,s), 19.77(1/2P,s).

TSPMS(m/z): 443(M⁺+1).

Example 19(S)-6-Amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using (1R)-amino-2-methylpropylphosphinic acid as astarting material.

¹H-NMR(D₂O): δ0.56(3H,d), 0.65(3H,d), 1.2-1.5(2H,m), 1.5-1.8(4H,m),1.8-2.1(1H,m), 2.4-2.7(2H,m), 2.7-3.0(4H,m), 3.78(1H,dd), 4.41(1H,dt),7.1-7.3(5H,m).

Example 20(S)-6-Amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) Diphenylmethylamine (4.00 ml) and cyclopentanone (2.06 ml) werestirred at 120° C. for 3 hours, and then the mixture was returned toroom temperature and added with tetrahydrofuran (2 ml) and phosphinicacid (1.8 g). The mixture was stirred at room temperature for 3 minutes,and then allowed to stand for 17 hours. Water (20 ml) was added to thereaction system, and the insoluble solid was collected by filtration andwashed with tetrahydrofuran, and then dried to obtain crude1-(diphenylmethylamino)cyclopentylphosphinic acid (1.53 g). Thiscompound was subjected to the measurement of molecular weight and thenused in the following reaction.

TSPMS(m/z): 316(M⁺+1).

(b) The crude 1-(diphenylmethylamino)cyclopentylphosphinic acid (1.53 g)obtained in the above step (a) was added with 47% aqueous hydrobromicacid (20 ml) and stirred at 100° C. for 2 hours. The reaction productwas extracted with water from the residue obtained by removing thesolvent from the reaction system under reduced pressure. The aqueouslayer was washed with diethyl ether and concentrated. The resulting oilwas dissolved in ethanol and added with propylene oxide (3 ml) and ethylacetate. The precipitated crystals were collected by filtration anddried to give 1-aminocyclopentylphosphinic acid (462 mg, 13%).

¹H-NMR(D₂O): δ1.6-1.8(6H,m), 2.0-2.1(2H,m), 6.83(1H,d).

TSPMS(m/z): 150(M⁺+1).

(c) In-the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using the 1-aminocyclopentylphosphinic acidobtained in the above step (b) as a starting material.

¹H-NMR(D₂O): δ1.4-1.6(6H,m), 1.7-2.0(6H,m), 2.0-2.2(2H,m), 2.55(2H,t),2.92(2H,t), 3.02(2H,t), 4.5-4.6(1H,m), 7.2-7.4(5H,m).

TSPMS(m/z): 427(M⁺+1).

Example 21(S)-6-Amino-2-((2-methyl-(1S)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((2-methyl-(1S)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using (1S)-amino-2-methylpropylphosphinic acid as astarting material.

¹H-NMR(D₂O): δ0.60(6H,d), 1.2-1.5(2H,m), 1.5-1.8(4H,m), 1.8-2.0(1H,m),2.5-2.7(2H,m), 2.8-3.0(4H,m), 3.79(1H,dd), 4.41(1H,dt), 7.1-7.4(5H,m).

³¹P-NMR(D₂O): δ18.6(1P,s).

FABMS(m/Z): 415(M⁺+1).

Example 226-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoicacid

(a) 4-Amino-1-butanol (5 g) was dissolved in water (50 ml) and cooled to0° C. The solution was added with 1 N aqueous sodium hydroxide (56.1 ml)and then with benzyl chloroformate (8 ml) and stirred at roomtemperature for 23 hours. 5 N aqueous sodium hydroxide (22.4 ml) andbenzyl chloroformate (16 ml) were further added to the mixture, andstirring was continued for 2 hours. The reaction system was cooled to 0°C. and adjusted to pH 4 with 5 N hydrochloric acid, and the organicsubstances were extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the precipitated crystals werewashed with diethyl ether to obtain 4-benzyloxycarbonylamino-1-butanol(8.15 g, 65%).

¹H-NMR(CDCl₃): δ1.59(4H,m), 1.73(1H,m), 3.24(2H,dd), 3.66(2H,dd),4.92(1H,s), 5.09(2H,s), 7.29-7.40(5H,m).

EIMS(m/z): 223(M⁺).

(b) The 4-benzyloxycarbonylamino-1-butanol (8.15 g) obtained in theabove step (a) and carbon tetrabromide (15.12 g) were dissolved inmethylene chloride (130.4 ml) and cooled with water. The mixture wasadded with triphenylphosphine (14.4 g) and returned to room temperature,and then stirred for 4 hours. The reaction system was concentrated underreduced pressure without any treatment, and the residue was purified bysilica gel column chromatography (400 g, hexane:ethyl acetate=5:2) toobtain 1-benzyloxycarbonylamino-4-bromobutane (10.4 g, 99.5%).

¹H-NMR(CDCl₃): δ1.58-1.72(2H,m), 1.84-1.94(2H,m), 3.18-3.28(2H,dd),3.42(2H,dd), 4.80(1H,s), 5.10(2H,s), 7.29-7.39(5H,m).

EIMS(m/z): 286(M⁺).

(c) An ethanol (130.2 ml) solution of sodium ethoxide (5.83 g) was addedwith diethyl malonate (13 ml) and stirred at room temperature for 5minutes. This solution was added with an ethanol (55.8 ml) solution ofthe 1-benzyloxycarbonylamino-4-bromobutane (4.9 g) obtained in the abovestep (b), and stirred at 40° C. for 20 hours. The reaction system wasconcentrated under reduced pressure without any treatment, and theresidue was added with saturated aqueous ammonium chloride, and then theorganic substances were extracted with ethyl acetate. The organic layerwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (1.2 kg, hexane:ethyl acetate=2:1) toobtain diethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (5.2 g, 83%).

¹H-NMR(CDCl₃): δ1.26(6H,t), 1.30-1.40(2H,m), 1.48-1.58(2H,m),1.87-1.94(2H,m), 3.19(2H,dd), 3.30(1H,dd), 4.19(4H,q), 4.83(1H,s),5.10(2H,s), 7.28-7.38(5H,m).

FABMS(m/z): 366(M⁺+1).

(d) An ethanol (10.2 ml) solution of the diethyl2-(4-benzyloxycarbonylaminobutyl)malonate (3.4 g) obtained in the abovestep (c) was added with an ethanol (6.8 ml) solution of potassiumhydroxide (584 mg), and the mixture was stirred at room temperature for26 hours. The reaction system was concentrated under reduced pressurewithout any treatment, and water was added to the residue. The aqueouslayer was washed with diethyl ether to remove impurities. The aqueouslayer was adjusted to pH 3 with 1 N hydrochloric acid, and then theorganic substances were extracted with ethyl acetate. The organic layerwas concentrated under reduced pressure to obtain monoethyl2-(4-benzyloxycarbonylaminobutyl)malonate (3.03 g, 96.5%).

¹H-NMR(CDCl₃): δ1.27(3H,t), 1.32-1.43(2H,m), 1.48-1.58(2H,m),1.86-1.96(2H,m), 3.11-3.25(2H,m), 3.36(1H,dd), 4.20(2H,q), 4.91(1H,s),5.09(2H,s), 7.28-7.39(5H,m), 7.50-8.35(1H,brs).

FABMS(m/z): 338(M⁺+1).

(e) The monoethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (3.03 g)obtained in the above step (d) was cooled to 0° C. and added with 36%formaldehyde solution (3 ml) and then with diethylamine (3 ml), and thenthe mixture was stirred at room temperature for 19.5 hours. Ethylacetate was added to the reaction system to extract the organicsubstances, and the organic layer was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(150 g, hexane:acetone=5:1) to obtain ethyl2-(4-benzyloxycarbonylaminobutyl)acrylate (1.69 g, 62%).

¹H-NMR(CDCl₃): δ1.30(3H,t), 1.47-1.56(4H,m), 2.32(2H,t), 3.22(2H,q),4.20(2H,q), 4.77(1H,s), 5.10(2H,s), 5.52(1H,s), 6.14(1H,s),7.29-7.37(5H,m).

TSPMS(m/z): 306(M⁺+1).

(f) The 2-methyl-1-(3-phenylpropanoyl)aminopropylphosphinic acid (255mg) obtained in (a) of Example 2 was added with hexamethyldisilazane(0.3 ml), and the mixture was stirred at 110° C. for 30 minutes. Themixture was then added with the ethyl2-(4-benzyloxycarbonylaminobutyl)acrylate (356 mg) obtained in the abovestep (e), and further stirred at the same temperature for 18 hours. Theorganic substances were extracted with ethyl acetate, and the extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and then the residue was purifiedby Sephadex LH-20 (300 cc, methylene chloride:methanol=1:1) to obtaincrude ethyl6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate(222 mg, 41%). This compound was used in the following reaction withoutfurther purification. (g) The crude ethyl6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate(222 mg) obtained in the above step (f) was dissolved in a mixed solventof ethanol:water (10:7) (3.4 ml). The mixture was added with 1 N aqueoussodium hydroxide (0.6 ml) and stirred at room temperature for 3 hours,at 50° C. for 2 hours, and then at room temperature for 16 hours. Thereaction mixture was acidified with hydrochloric acid and the organicsubstances were extracted with ethyl acetate, and then the extract waswashed with saturated brine and dried over anhydrous magnesium sulfate.The residue was concentrated to obtain crude6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoicacid (181 mg, 86%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/Z): 547(M⁺+1).

(h) The crude6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoicacid (181 mg) obtained in the above step (g) was dissolved in a mixedsolvent of dioxane and water (1:1) (4 ml). The solution was added withpalladium hydroxide (37 mg), and the mixture was stirred under ahydrogen atmosphere at room temperature for 4 hours. The reactionmixture was filtered with celite and the filtrate was concentrated. Theresidue was purified with HP-20 (Diaion, 20 cc, methanol:water=1:9 toacetone:water=1:1) to obtain the title compound:6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoicacid (74 mg, 54%) (a diastereoisomeric mixture of 3:1).

¹H-NMR(D₂O): δ0.6-0.8(6H,m), 1.2-1.7(8H,m), 2.0-2.2(1H,m),2.4-2.7(3H,m), 2.8-3.0(4H,m), 3.6-3.8(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ37.9(3/4P,s), 38.3(1/4P,s).

TSPMS(m/z): 413(M⁺+1).

Example 23(S)-6-Amino-2-((3,3-dimethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((3,3-dimethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1^(-amino-)3,3-dimethylbutylphosphinic acid as a starting material.

1H-NMR(D₂O): δ0.77(9/2H,s), 0.79(9/2H,s), 1.3-1.6(3H,m), 1.7-1.9(5H,m),2.5-2.6(2H,m), 2.9-3.0(2H,m), 3.03(2H,t), 4.1-4.2(1H,m), 4.4-4.5(1H,m),7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ20.1(1/2P,s), 20.8(1/2P,s).

TSPMS(m/z): 443(M⁺+1).

Example 24(S)-6-Amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl(hydroxyphosphinoyl)oxy)hexanoicacid

(a) Benzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate (3.4 g),which is obtainable from 6-amino-2-hydroxyhexanoic acid described inChem. Pharm. Bull., 621(1976) in a conventional manner, was dissolved indichloromethane (34 ml), and the solution was added with phosphorustrichloride (3.43 ml) at 0° C. and stirred for 1 hour. The reactionsystem was added with ice and further stirred for 30 minutes, and thenthe organic substances were extracted with ethyl acetate. The organiclayer was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (170 g, hexane:ethylacetate=1:1 to chloroform:methanol:acetic acid=2:1:0.01) to obtainbenzyl 6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate(3.68 g, 92%).

¹H-NMR(CDCl₃): δ1.20-1.55(4H,m), 1.56-1.91(2H,m), 2.97(2H,brs),4.77(1H,brs), 4.94(1H,d), 5.16(1H,d), 5.00(2H,s), 5.67(1H,brs),6.88(1H,d), 7.16-7.29(10H,m).

TSPMS(m/z): 436(M⁺+1).

(b) An acetonitrile (29.7 ml) solution of the benzyl6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate (2.97 g)obtained in the above step (a) was added with benzyl alcohol (3.53 ml)and a pyridine (11.9 ml)-acetonitrile (11.9 ml) mixed solution ofpivaloyl chloride (4.20 ml), and the mixture was stirred at roomtemperature for 1 hour. Saturated aqueous ammonium chloride was added tothe reaction system, and the organic substances were extracted withethyl acetate. The organic layer was concentrated under reducedpressure, and pyridine was removed by azeotropic distillation usingtoluene. The residue was roughly purified by silica gel (Kanto KagakuCo., 60 N, spherical, neutral) chromatography (300 g, hexane:ethylacetate=3:2) to obtain crude benzyl6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (2.45 g,68%). This compound was subjected to the measurement of molecular weightand then used in the following reaction without further purification.

TSPMS(m/z): 526(M⁺+1).

(c) Isobutylaldehyde (2.8 ml) was dissolved in tetrahydrofuran (10 ml),and the solution was added with 4-methoxybenzylamine (1 ml) and thenstirred at 60° C. for 2 hours. The imine generation was observed by¹H-NMR, and then the reaction mixture was concentrated under reducedpressure to obtain crude (4-methoxybenzyl)-N-(2-methylpropylidene)amine.

¹H-NMR(CDCl₃): δ1.10(6H,d), 2.43-2.56(1H,m), 3.79(3H,s), 4.49(2H,s),6.86(2H,d), 7.17(2H,d), 7.63(1H,dt).

(d) To the crude benzyl6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (192.5mg) obtained in the above step (b), a tetrahydrofuran (5.4 ml) solutionof the crude (4-methoxybenzyl)-N-(2-methylpropylidene)amine obtained in(c) above was added, and the mixture was stirred at room temperature for21 hours. To the reaction system, 10% aqueous citric acid was added, andthen the organic substances were extracted with ethyl acetate. Theorganic layer was concentrated under reduced pressure, and then theresidue was roughly purified by silica gel (Kanto Kagaku Co. 60 N,spherical, neutral) chromatography (20 g, hexane:acetone=2:1) to obtaincrude benzyl(S)-6-benzyloxycarbonylamino-2-((1-((4-methoxy)benzylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)hexanoate(176.2 mg, 67%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

FABMS(m/z): 717(M⁺+1).

(e) The crude benzyl(S)-6-benzyloxycarbonylamino-2-((1-((4-methoxy)benzylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)hexanoate(557.4 mg) obtained in the above step (d) was dissolved in a mixedsolvent of acetonitrile and water (4:1) (5.6 ml). Cerium(IV) diammoniumnitrate was dissolved in a mixed solvent of acetonitrile and water (4:1)(5.6 ml), and the resulting solution was added to the reaction system.The mixture was stirred at room temperature for 1.5 hours. The mixturewas cooled to 0° C. and added with saturated aqueous sodium thiosulfate,and further stirred at room temperature for 30 minutes. The organicsubstances were extracted with ethyl acetate, and the organic layer wasconcentrated under reduced pressure, and then the residue was roughlypurified by silica gel column chromatography (25 g, hexane:ethylacetate:acetic acid=250:50:1.5 to chloroform:methanol=30:1) to obtaincrude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(271 mg, 62%). This compound was examined in the molecular weight andthen used in the following reaction without further purification.

ESIMS(m/z): 597(M⁺+1).

(f) 4-Phenylbutanoic acid (58.2 mg) was dissolved in methylene chloride(1 ml), and the solution was added with diisopropylethylamine (92.6 ml)and benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophophate and then stirred at room temperature for 7 minutes.The crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(105.7 mg) obtained in the above step (e) was dissolved in methylenechloride (640 ml), and the reaction mixture was added with the abovesolution and stirred at room temperature for 22 hours. Saturated aqueousammonium chloride was added to the reaction mixture, and the organicsubstances were extracted with ethyl acetate, and then the organic layerwas concentrated under reduced pressure. The residue was roughlypurified by thin-layer chromatography to obtain benzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(4-phenylbutanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate(43.9 mg, 33%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 743(M⁺+1).

(g) The benzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(4-phenylbutanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate(43.9 mg) obtained in the above step (f) was dissolved in a mixedsolvent of dioxane and water (3:1) (439 ml), and the solution was addedwith palladium hydroxide (8.8 mg) and stirred under a hydrogenatmosphere at room temperature for 18 hours. The reaction mixture wasfiltered with celite, and the filtrate was concentrated under reducedpressure. The residue was purified by HP-20 (Diaion, 5 g, water tomethanol) to obtain the title compound:(S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl(hydroxyphosphinoyl)oxy)hexanoicacid (17.5 mg, 70%, a diastereoisomeric mixture of 1:1).

1H-NMR(D₂O): δ0.74-0.86(6H,m), 1.16-1.41(2H,m), 1.45-1.59(2H,m),1.59-1.67(2H,m), 1.73-1.84(2H,m), 1.90-2.07(1H,m), 2.12-2.27(2H,m),2.49-2.57(2H,m), 2.83(2H,q), 3.37-3.89(1H,m), 4.32-4.42(1H,m),7.10-7.26(5H,m).

³¹P-NMR(D₂O): δ18.64(1/2P,s), 19.62(1/2P,s).

FABMS(m/z): 429(M⁺+1).

Example 25(S)-6-Amino-2-((4,4,4-trifluoro-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((4,4,4-trifluoro-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-4,4,4-trifluorobutylphosphinic acid as a starting material.

1H-NMR(D₂O): δ1.4-1.9(9H,m), 1.9-2.0(1H,m), 2.6-2.7(2H,m),2.9-3.1(4H,m), 3.9-4.0(1H,m), 4.5-4.6(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ17.7(1/2P,s), 18.4(1/2P,s).

TSPMS(m/z): 469(M⁺+1).

Example 26(S)-6-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 24, the title compound:(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using 3-phenylpropanoic acid instead of4-phenylbutanoic acid used in the step (f) of Example 24. The spectrumdata of the resulting compound showed similar values to those of thecompound obtained in Example 2.

¹H-NMR(D₂O): δ0.56(3/2H,d), 0.59(3H,m), 0.66(3/2H,d), 1.2-1.5(2H,m),1.6-1.8(4H,m), 1.8-2.0(1H,m), 2.5-2.7(2H,m), 2.8-3.0(4H,m),3.7-3.9(1H,m), 4.3-4.5(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ18.7(1/2P,s), 19.7(1/2P,s).

TSPMS(m/z): 415(M⁺+1).

Example 27(S)-7-Amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid

In the same manner as the method of Example 2, the title compound:(S)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid was obtained by using benzyl(S)-7-benzyloxycarbonylamino-2-hydroxyheptanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step (b) ofExample 2, and using the 1-aminocyclopentylphosphinic acid obtained inthe step (b) of Example 20.

¹H-NMR(D₂O): δ1.25-1.34(6H,m), 1.45(2H,m), 1.55(2H,m), 1.65(2H,m),1.78(2H,m), 1.93(2H,m), 2.44(2H,m), 2.79(2H,m), 2.89(2H,m), 4.40(1H,m),7.15-7.27(5H,m).

³¹P-NMR(D₂O): δ23.41(1P,s).

TSPMS(m/z): 441(M⁺+1).

Example 28(R)-7-Amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid

In the same manner as the method of Example 2, the title compound:(R)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoicacid was obtained by using benzyl(R)-7-benzyloxycarbonylamino-2-hydroxyheptanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step (b) ofExample 2, and using the 1-aminocyclopentylphosphinic acid obtained in(b) of Example 20.

¹H-NMR(D₂O): δ1.25-1.34(6H,m), 1.45(2H,m), 1.55(2H,m), 1.65(2H,m),1.78(2H,m), 1.93(2H,m), 2.44(2H,m), 2.79(2H,m), 2.89(2H,m), 4.40(1H,m),7.15-7.27(5H,m).

³¹P-NMR(D₂O): δ23.41(1P,s).

TSPMS(m/z): 441(M⁺+1).

Example 29(S)-7-Amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)heptanoicacid

In the same manner as the method of Example 2, the title compound:(S)-7-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)heptanoicacid was obtained by using (1R)-amino-2-methylphosphinic acid instead ofamino-2-methylphosphinic acid used in the step (a) of Example 2, andusing benzyl (S)-7-benzyloxycarbonylamino-2-hydroxyheptanoate instead ofbenzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step(b) of Example 2.

¹H-NMR(D₂O): δ0.61(6H,m), 1.24-1.32(4H,m), 1.55(4H,m), 1.93(1H,m),2.53(2H,m), 2.83(4H,m), 3.75(1H,dd), 4.38(1H,m), 7.13-7.27(5H,m).

³¹P-NMR(D₂O): δ19.56(1P,s).

TSPMS(m/z): 429(M⁺+1).

Example 302-(2-Methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)-4-(piperidin-4-yl)butanoicacid

In the same manner as the method of Example 2, the title compound:2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)-4-(piperidin-4-yl)butanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using(1R)-amino-2-methylphosphinic acid instead of amino-2-methylphosphinicacid used in the step (a) of Example 2, and using benzyl4-(1-benzyloxycarbonylpiperidin-4-yl)-2-hydroxybutanoate instead ofbenzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step(b) of Example 2.

¹H-NMR(D₂O): δ0.53-0.63(6H,m), 1.27(4H,m), 1.48(1H,m), 1.64(2H,m),1.84(3H,m), 2.57(2H,m), 2.84(4H,m), 3.25(2H,m), 2.72(1H,m),4.37(1H,brs), 7.14-7.27(5H,m).

³¹P-NMR(D₂O): δ18.49(1/2P,s), 19.50(1/2P,s).

TSPMS(m/z): 455(M⁺+1).

Example 311-(trans-(4-Aminomethylcyclohexyl))-1-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)aceticacid

In the same manner as the method of Example 2, the title compound:1-(trans-(4-aminomethylcyclohexyl))-1-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)aceticacid (a diastereoisomeric mixture of 1:1) was obtained by using(1R)-amino-2-methylphosphinic acid instead of amino-2-methylphosphinicacid used in the step (a) of Example 2, and using1-trans-(4-(benzyloxycarbonylaminomethyl)cyclohexyl)-1-hydroxyaceticacid instead of benzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoatein (b) of Example 2.

¹H-NMR(D₂O): δ0.53-0.66(6H,m), 0.92(2H,m), 1.16(2H,m), 1.49-1.94(7H,m),2.58(2H,m), 2.74-2.87(4H,m), 3.75(1H,m), 4.24(1H,m), 7.16(5H,m).

³¹P-NMR(D₂O): δ19.12(1/2P,s), 20.10(1/2P,s).

TSPMS(m/z): 455(M⁺+1).

Example 323-Aminoacetoxy-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)propanoicacid

In the same manner as the method of Example 2, the title compound:3-aminoacetoxy-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)propanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using(1R)-amino-2-methylphosphinic acid instead of amino-2-methylphosphinicacid used in the step (a) of Example 2, and using benzyl3-benzyloxycarbonylaminoacetoxy-2-hydroxypropanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step (b) ofExample 2.

¹H-NMR(D₂O): δ0.54-0.64(6H,m), 2.55(2H,m), 2.86(2H,m), 3.78(3H,m),3.99(2H,m), 4.35(1H,m), 7.14-7.28(5H,m).

³¹P-NMR(D₂O): δ18.77(1/2P,s), 19.77(1/2P,s).

TSPMS(m/z): 431(M⁺+1).

Example 338-Amino-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)octanoicacid

In the same manner as the method of Example 2, the title compound:8-amino-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)octanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using(1R)-amino-2-methylphosphinic acid instead of amino-2-methylphosphinicacid used in the step (a) of Example 2, and using benzyl8-benzyloxycarbonylamino-2-hydroxyoctanoate instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step (b) ofExample 2.

¹H-NMR(D₂O): δ0.52-0.63(6H,m), 1.15-1.24(6H,m), 1.51(4H,m), 1.91(1H,m),2.55(2H,m), 2.83(4H,m), 3.74(1H,m), 4.38(1H,m), 7.13-7.27(5H,m).

³¹P-NMR(D₂O): δ18.52(1/2P,s), 19.52(1/2P,s).

TSPMS(m/z): 443(M⁺+1).

Example 34(S)-6-Amino-2-((1-phenyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-phenyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 3:5) was obtained by using1-amino-1-phenylmethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ1.3-1.5(2H,m), 1.6-1.8(4H,m), 2.6-2.8(2H,m),2.8-3.0(4H,m), 4.0-4.1(1H,m), 4.4-4.5(1H,m), 7.1-7.3(10H,m).

³¹P-NMR(D₂O): δ15.1(3/8P,s), 16.2(5/8P,s).

TSPMS(m/z): 449(M⁺+1).

Example 35(S)-6-Amino-2-((1-(3-phenylpropanoylamino)-1-(tetrahydropyran-4-yl)methyl)(hydroxyphosphinoyl)oxy)bexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-(3-phenylpropanoylamino)-1-(tetrahydropyran-4-yl)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-(tetrahydropyran-4-yl)methylphosphinic acid as a startingmaterial.

¹H-NMR(D₂O): δ0.8-1.1(2H,m), 1.3-1.6(4H,m), 1.6-2.0(5H,m),2.6-2.8(2H,m), 2.9-3.1(4H,m), 3.2-3.4(2H,m), 3.7-3.9(3H,m),4.5-4.6(1H,m), 7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ17.4(1/2P,s), 18.6(1/2P,s).

FABMS(m/z): 457(M⁺+1).

Example 36(S)-5-Amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)pentanoicacid

In the same manner as the method of Example 2, the title compound:(S)-5-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)pentanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-3-methylbutylphosphinic acid as a starting material, and usingbenzyl (S)-5-benzyloxycarbonylamino-2-hydroxypentanoate instead ofbenzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) of Example2.

¹H-NMR(D₂O): δ0.7-0.8(6H,m), 0.8-0.9(1H,m), 1.2-1.5(2H,m),1.7-1.9(4H,m), 2.6-2.7(2H,m), 2.9-3.1(4H,m), 4.0-4.1(1H,m),4.5-4.6(1H,m), 7.3-7.4(5H,m).

³¹P-NMR(D₂O): δ20.1(1/2P,s), 20.7(1/2P,s).

TSPMS(m/z): 415(M⁺+1).

Example 37(S)-6-Amino-2-((2-hydroxy-1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((2-hydroxy-1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-2-benzyloxyethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ1.4-1.6(2H,m), 1.6-1.9(4H,m), 2.6-2.7(2H,m),2.9-3.1(4H,m), 3.5-3.7(1H,m), 3.7-3.9(1H,m), 4.1-4.2(1H,m),4.5-4.6(1H,m), 7.3-7.4(5H,m).

³¹P-NMR(D₂O): δ15.9(1/2P,s), 16.4(1/2P,s).

TSPMS(m/z): 403(M⁺+1).

Example 38(S)-6-Amino-2-((1-cycloheptyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-cycloheptyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-cycloheptylmethylphosphinic acid as a starting material.

¹H-NMR(D₂O): δ0.7-1.0(2H,m), 1.2-1.9(17H,m), 2.6-2.8(2H,m),2.9-3.1(4H,m), 3.8-4.0(1H,m), 4.4-4.5(1H,m), 7.3-7.4(5H,m).

³¹P-NMR(D₂O): δ18.8(1/2P,s), 19.7(1/2P,s).

TSPMS(m/z): 469(M⁺+1).

Example 39(S)-6-Amino-2-((1-(piperidin-4-yl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((1-(piperidin-4-yl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-(1-(4-nitrobenzyloxcarbonyl)piperidin-4-yl)methylphosphinicacid as a starting material.

¹H-NMR(D₂O): δ0.9-1.5(5H,m), 1.5-2.0(6H,m), 2.6-2.9(4H,m),2.9-3.0(4H,m), 3.1-3.3(2H,m), 3.8-3.9(1H,m), 4.4-4.5(1H,m),7.3-7.4(5H,m).

³¹P-NMR(D₂O): δ16.7(1/2P,s), 17.8(1/2P,s).

TSPMS(m/z): 456(M⁺+1).

Example 40(S)-6-Amino-2-((4-amino-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-((4-amino-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 4:5) was obtained by using1-amino-4-(4-nitrobenzyloxycarbonyl)aminobutylphosphinic acid as astarting material.

¹H-NMR(D₂O): δ1.1-1.6(5H,m), 1.6-1.8(5H,m), 2.6-2.7(4H,m),2.9-3.0(4H,m), 3.9-4.0(1H,m), 4.5-4.6(1H,m), 7.3-7.4(5H,m).

³¹P-NMR(D₂O): δ18.3(4/9P,s), 19.0(5/9P,s).

TSPMS(m/z): 430(M⁺+1).

Example 41(S)-6-Amino-2-((1-(4-methylcyclohexyl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-(1-(4-methylcyclohexyl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using1-amino-1-(4-methylcyclohexyl)methylphosphinic acid as a startingmaterial.

¹H-NMR(D₂O): δ0.4-0.9(7H,m), 1.0-1.1(1H,m), 1.3-1.8(11H,m),2.6-2.8(2H,m), 2.9-3.1(4H,m), 3.8-3.9(1H,m), 4.4-4.5(1H,m),7.2-7.4(5H,m).

³¹P-NMR(D₂O): δ18.7(1/2P,s), 19.9(1/2P,s).

TSPMS(m/z): 469(M⁺+1).

Example 42(S)-6-Amino-2-(((1R)-((2S)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) N-Benzyloxycarbonyl-L-phenylalanine (56.3 mg) and the crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxyearbonylaminohexanoate(93.6 mg) obtained in (e) of Example 24 were dissolved in methylenechloride (1.5 ml), and the solution was added with diisopropylethylamine(54.6 ml) and benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (83.3 mg). The mixture was stirred under an argonatmosphere at room temperature for 22 hours. Saturated aqueous sodiumchloride was added to the reaction system, and then the organicsubstances were extracted with ethyl acetate. The organic layer wasconcentrated under reduced pressure, and the residue was purified bythin-layer chromatography (chloroform:acetone=5:1) to obtain benzyl(S)-2-(1-(((2S)-benzyloxyamino-3-phenylpropanoylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(105.8 mg, 76.8%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 878(M⁺+1).

(b) The benzyl(S)-2-(1-(((2S)-benzyloxyamino-3-phenylpropanoylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(28.8 mg) obtained in the above step (a) was dissolved in a mixedsolvent of dioxane:water=3:1 (288 ml), and the solution was added withpalladium hydroxide (5.8 mg) and then stirred under a hydrogenatmosphere at room temperature for 17 hours. The reaction mixture wasfiltered with celite, and the filtrate was concentrated under reducedpressure. The residue was purified by thin-layer chromatography (ethylacetate:methanol:water=2:2:1) and HP20 (Diaion, water to methanol) toobtain the title compound:(S)-6-amino-2-(((1R)-((2S)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (7.5 mg).

¹H-NMR(D₂O): δ0.82(3H,d), 0.86(3H,d), 1.28-1.45(2H,m), 1.50-1.63(2H,m),1.64-1.78(2H,m), 2.04-2.15(1H,m), 2.90(2H,t), 2.93(1H,dd), 3.17(1H,dd),3.84(1H,dd), 4.09(1H,dd), 4.34-4.41(1H,m), 7.22-7.32(5H,m).

³¹P-NMR(D₂O): δ18.82(1P,s).

TSPMS(m/z): 430(M⁺+1).

Example 43(S)-6-Amino-2-((2-methyl-(1R)-phenylacetylaminopropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) The crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(88.5 mg) obtained in the step (e) of Example 24 was dissolved inmethylene chloride (1.77 ml), and the solution was added withtriethylamine (41.3 μl) and phenylacetyl chloride (21.6 μl) and thenstirred under an argon atmosphere at room temperature for 19 hours.Saturated aqueous ammonium chloride was added to the reaction system andthe organic substances were extracted with ethyl acetate, and then theorganic layer was concentrated under reduced pressure. The residue waspurified by thin-layer chromatography (chloroform:acetone=5:1) to obtainbenzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-phenylacetylaminopropyl)(benzyloxyphosphinoyl)oxy)hexanoate(60.4 mg, 56%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 715(M⁺+1).

(b) In the same manner as the method of (b) in Example 42, the titlecompound:(S)-6-amino-2-((2-methyl-(1R)-phenylacetylaminopropyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using the benzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-phenylacetylaminopropyl)(benzyloxyphosphinoyl)oxy)hexanoateobtained in the above step (a) as a starting material.

¹H-NMR(D₂O): δ0.76(3H,d), 0.81(3H,d), 1.20-1.34(2H,m), 1.48-1.59(2H,m),1.60-1.68(2H,m), 1.98-2.11(1H,m), 2.84(2H,t), 3.50(1H,d), 3.59(1H,d),3.85(1H,dd), 4.45-4.51(1H,m), 7.21-7.33(5H,m).

³¹P-NMR(D₂O): δ19.43(1P,s).

FABMS(m/z): 401(M⁺+1).

Example 44(S)-6-Amino-2-((1-((2R)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

N-Benzyloxycarbonyl-D-phenylalanine was used instead ofN-benzyloxycarbonyl-L-phenylalanine in the step (a) of Example 42 toobtain the title compound:(S)-6-amino-2-((1-((2R)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 5:2).

¹H-NMR(D₂O): δ0.43-0.51(4H,m), 0.73-0.84(2H,m), 1.23-1.43(2H,m),1.47-1.6(2H,m), 1.60-1.74(2H,m), 1.80-2.05(1H,m), 2.79-2.91(2H,m),2.91-3.14(2H,m), 3.67-3.76(2/7H,m), 3.79-3.89(2/7H,m), 3.98-4.14(1H,m),4.32-4.44(1H,m), 7.16-7.33(5H,m).

³¹P-NMR(D₂O): δ17.90(2/7P,s), 19.37(5/7P,s).

TSPMS(m/z): 430(M⁺+1).

Example 45(S)-6-Amino-2-((1-(3-cyclopentylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((1-(3-cyclopentylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 2:5) was obtained by using3-cyclopentylpropionyl chloride instead of phenylacetyl chloride in (a)of Example 43.

¹H-NMR(D₂O): δ0.78-0.88(6H,m), 1.21-1.74(17H,m), 1.94-2.13(1H,m),2.14-2.32(2H,m), 2.91(2H,t), 3.79-3.90(1H,m), 4.36-4.46(1H,m).

³¹P-NMR(D₂O): δ18.76(5/7P,s), 19.67(2/7P,s).

TSPMS(m/z): 407(M⁺+1).

Example 46(S)-6-Amino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) 2,4-Difluorobenzoic acid (153.5 mg) and the crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(144.8 mg) obtained in (e) of Example 24 were dissolved indimethylformamide (3 ml), and the reaction system was cooled to 0° C.The reaction mixture was added with diisopropylethylamine (250 μl) andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(429.3 mg) and then stirred under an argon atmosphere at roomtemperature for 2 hours. Saturated aqueous ammonium chloride was addedto the reaction system, and then the organic substances were extractedwith ethyl acetate. The organic layer was concentrated under reducedpressure, and the residue was roughly purified by thin-layerchromatography (chloroform:acetone=5:1) to obtain benzyl(S)-6-benzyloxycarbonylamino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)hexanoate(77.8 mg, 43.5%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 737(M⁺+1).

(b) In the same manner as the method of (b) in Example 42, the titlecompound:(S)-6-amino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:2) was obtained by using thebenzyl(S)-6-benzyloxycarbonylamino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)hexanoateobtained in (a) above as a starting material.

¹H-NMR(D₂O): δ0.87(2H,d), 0.92(4H,d), 1.20-1.43(2H,m), 1.49-1.59(2H,m),1.62-1.71(2H,m), 2.05-2.23(1H,m), 2.85(2H,t), 4.07(2/3H,dd),4.11(1/3H,dd), 4.38-4.46(1H,m), 6.95-7.02(3H,m), 7.60-7.69(1H,m).

³¹P-NMR(D₂O): δ18.03(2/3P,s), 18.70(1/3P,s).

TSPMS(m/z): 423(M⁺+1).

Example 47(S)-6-Amino-2-((1-benzoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 46, the title compound:(S)-6-amino-2-((1-benzoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:8) was obtained by using benzoicacid instead of 2,4-difluorobenzoic acid used in the step (a) of Example46.

¹H-NMR(D₂O): δ0.87(3H,d), 0.94(3H,d), 1.20-1.41(2H,m), 1.43-1.57(2H,m),1.62-1.71(2H,m), 2.03-2.25(1H,m), 2.78(2H,t), 4.06(8/9H,d),4.13(1/9H,d), 4.40-4.47(1H,m), 7.45(2H,t), 7.53(1H,t), 7.75(1H,d).

³¹P-NMR(D₂O): δ18.42(8/9P,s), 19.32(1/9P,s).

FABMS(m/z): 387(M⁺+1).

Example 48(S)-6-Amino-2-((1-(3-(2-methoxyphenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 42, the title compound:(S)-6-amino-2-((1-(3-(2-methoxyphenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:3) was obtained by using3-(2-methoxyphenyl)propanoic acid instead ofN-benzyloxycarbonyl-L-phenylalanine used in the step (a) of Example 42.

¹H-NMR(D₂O): δ0.53-0.64(6H,m), 1.21-1.42(2H,m), 1.50-1.61(2H,m),1.61-1.69(2H,m), 1.81-1.97(1H,m), 2.40-2.50(1H,m), 2.57-2.64(1H,m),2.75-2.85(2H,m), 2.88(2H,t), 3.74(3H,s), 3.71-3.79(1H,m),4.35-4.42(1H,m), 6.85(1H,t), 6.92(1H,d), 7.11(1H,dd), 7.16(1H,t).

³¹P-NMR(D₂O): δ18.88(3/4P,s), 19.70(1/4P,s).

TSPMS(m/z): 387(M⁺+1).

Example 49(S)-6-Amino-2-((1-(4-methoxyphenyl)acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 42, the title compound:(S)-6-amino-2-((1-(4-methoxyphenyl)acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 4:1) was obtained by using4-methoxyphenylacetic acid instead ofN-benzyloxycarbonyl-L-phenylalanine used in the step (a) of Example 42.

¹H-NMR(D₂O): δ0.73(3H,d), 0.82(3H,d), 1.22-1.42(2H,m), 1.50-1.62(2H,m),1.62-1.71(2H,m), 1.95-2.10(1H,m), 2.90(2H,t), 3.42(1H,d), 3.54(1H,d),3.73(3H,s), 3.80-3.86(1H,m), 4.36-4.47(1H,m), 6.89(2H,d), 7.22(2H,d).

³¹P-NMR(D₂O): δ18.51(1/5P,s), 19.47(4/5P,s).

TSPMS(m/z): 431(M⁺+1).

Example 50(S)-6-Amino-2-((1-heptanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((1-heptanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 4:5) was obtained by usingn-heptanoyl chloride instead of phenylacetyl chloride used in the step(a) of Example 43.

¹H-NMR(D₂O): δ0.73(3H,t), 0.80(6H,dt), 1.10-1.40(8H,m), 1.40-1.70(6H,m),1.90-2.11(1H,m), 2.12-2.27(2H,m), 2.88(2H,t), 3.76-3.86(1H,m),4.33-4.44(1H,m).

³¹P-NMR(D₂O): δ18.86(5/9H,s), 19.71(4/9H,s).

TSPMS(m/z): 395(M⁺+1).

Example 51(S)-6-Amino-2-((1-(2-amino-2-phenylacetylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 42, the title compound:(S)-6-amino-2-((1-(2-amino-2-phenylacetylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 3:4:2:1) was obtained by usingN-benzyloxycarbonyl-L-phenylglycine instead ofN-benzyloxycarbonyl-L-phenylalanine used in the above (a) of Example 42.

¹H-NMR(D₂O): δ0.46-0.87(6H,m), 1.09-1.40(2H,m), 1.40-1.72(4H,m),1.82-2.13(1H,m), 2.76-2.91(2H,m), 3.75-3.90(1H,m), 4.05(0.2H,dq),4.27(0.3H,dq), 4.40(0.5H,dq), 4.69-4.90(1H,m), 7.28-7.41(5H,m).

³¹P-NMR(D₂O): δ20.51(3/10P,s), 20.67(4/10P,s), 21.03(2/10P,s),21.83(1/10P,s).

TSPMS(m/z): 416(M⁺+1).

Example 52(S)-6-Amino-2-((2-methyl-1-((pyridin-2-yl)acetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 42, the title compound:(S)-6-amino-2-((2-methyl-1-((pyridin-2-yl)acetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:5) was obtained by using2-pyridyl acetate hydrochloride instead ofN-benzyloxycarbonyl-L-phenylalanine used in the step (a) of Example 42.

¹H-NMR(D₂O): δ0.77(3H,d), 0.78(3H,d), 1.20-1.42(2H,m), 1.46-1.59(2H,m),1.60-1.71(2H,m), 1.93-2.11(1H,m), 2.86(2H,t), 3.70-3.79(2H,m),3.80-3.90(1H,m), 4.36-4.46(1H,m), 7.29(1H,dd), 7.37(1H,d), 7.78(1H,t),8.38(1H,d).

³¹P-NMR(D₂O): δ18.43(5/6P,s), 19.10(1/6P,s).

TSPMS(m/z): 402(M⁺+1).

Example 53(S)-6-Amino-2-((1-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 46, the title compound:(S)-6-amino-2-((1-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 5:1) was obtained by using4-methoxybenzoic acid instead of 2,4-difluorobenzoic acid used in thestep (a) of Example 46.

¹H-NMR(D₂O): δ0.79-0.90(6H,m), 1.10-1.31(2H,m), 1.36-1.49(2H,m),1.54-1.64(2H,m), 2.06-2.19(1H,m), 2.71(2H,t), 3.74(3H,s), 3.99(1/6H,dd),4.05(5/6H,dd), 4.35-4.43(1H,m), 6.95(2H,d), 7.68(2H,d).

³¹P-NMR(D₂O): δ18.64(1/6P,s), 19.52(5/6P,s).

TSPMS(m/z): 417(M⁺+1).

Example 54(S)-6-Amino-2-(((1R)-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) (1R)-Amino-2-methylpropylphosphinic acid (314.4 mg) was dissolved ina mixed solvent of water:dioxane=1:2 (943 μl) and cooled to 0° C., andthen added with 5 N aqueous sodium hydroxide (458.6 μl). Then 5 Naqueous sodium hydroxide (917.2 μl) and 4-methoxybenzoyl chloride (782.2mg) were simultaneously added dropwise to the reaction system over 10minutes. The mixture was stirred for 1 hour while being kept at 0° C.,and then at room temperature for 3 hours. 5 N Hydrochloric acid wasadded to the mixture to reduce the pH to 2, and the organic substanceswere extracted with ethyl acetate. The organic layer was concentratedunder reduced pressure, and precipitated crystals were washed withdiethyl ether to obtain(1R)-(4-methoxybenzoylamino)-2-methylpropylphosphinic acid (558.6 mg,89.8%). This compound was subjected to the measurement of molecularweight and then used in the following reaction without furtherpurification.

FABMS(m/z): 272(M⁺+1).

(b) In the same manner as the method of Example 2, the title compound:(S)-6-amino-2-(((1R)-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using the(1R)-(4-methoxybenzoylamino)-2-methylpropylphosphinic acid obtained inthe above step (a) instead of2-methyl-1-(3-phenylpropanoylamino)propylphosphinic acid used in thestep (b) of Example 2.

¹H-NMR(D₂O): δ0.89(3H,d), 0.91(3H,d), 1.12-1.34(2H,m), 1.38-1.48(2H,m),1.56-1.64(2H,m), 2.10-2.21(1H,m), 2.73(2H,t), 3.77(3H,s),4.07,4.11(1H,d), 4.38-4.44(1H,m), 6.97(2H.,d), 7.72(2H,d).

³¹P-NMR(D₂O): δ19.49(1P,s).

TSPMS(m/z): 417(M⁺+1).

Example 55(S)-6-Amino-2-((1-dodecanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((1-dodecanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by usingn-dodecanoyl chloride instead of phenylacetyl chloride used in the step(a) of Example 43.

¹H-NMR(D₂O): δ0.73(3H,t), 0.78-0.89(6H,m), 1.10-1.40(18H,m),1.41-1.69(6H,m), 2.00-2.32(3H,m), 2.87(2H,m), 3.78-3.93(1H,m),4.30-4.47(1H,m).

³¹P-NMR(D₂O): δ18.97(1/2P,s), 19.80(1/2P,s).

TSPMS(m/z): 465(M⁺+1).

Example 56(S)-2-((1-Acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)-6-aminohexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-2-((1-acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)-6-aminohexanoicacid (a diastereoisomeric mixture of 1:3) was obtained by using acetylchloride instead of phenylacetyl chloride in (a) of Example 43.

¹H-NMR(D₂O): δ0.78(3H,d), 0.82(3H,d), 1.24-1.46(2H,m), 1.52-1.62(2H,m),1.63-1.73(2H,m), 1.95(3H,s), 1.95-2.07(1H,m), 2.91(2H,t),3.75-3.86(1H,m), 4.36-4.46(1H,m).

³¹P-NMR(D₂O): δ21.19(3/4P,s), 22.30(1/4P,s).

TSPMS(m/z): 325(M⁺+1).

Example 57(S)-6-Amino-2-((1-(3-(4-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) 4-Nitrobenzaldehyde (1 g) was dissolved in methylene chloride (20ml), and the reaction system was cooled to 0° C. The solution was addedwith carboethoxy-methylenetriphenylphospholan (2.56 g) and stirred at 0°C. for 1 hour. The reaction system was concentrated under reducedpressure without any treatment, and the residue was purified by silicagel column chromatography (50 g, hexane:ethyl acetate=4:1) to obtainethyl 3-(4-nitrophenyl)acrylate (1.27 g, 86%).

¹H-NMR(CDCl₃): δ1.36(3H,t), 4.30(2H,q), 6.56(1H,d), 7.67(1H,d),7.71(1H,d), 8.25(1H,d).

EIMS(m/z): 221(M⁺).

(b) The ethyl 3-(4-nitrophenyl)acrylate (512.8 mg) obtained in the abovestep (a) was dissolved in dioxane (5.1 ml), and the solution was addedwith 5 N sodium hydroxide (2.78 ml) and stirred at room temperature for3.5 hours. Separation and extraction with diethyl ether was made toremove impurities, and then 5 N hydrochloric acid was added to theaqueous layer to reduce the pH to 2. The precipitated crystals werecollected by filtration to obtain 3-(4-nitrophenyl)acrylic acid (270.1mg, 60.3%).

¹H-NMR(DMSO): δ6.75(1H,d), 7.70(1H,d), 7.98(1H,d), 8.24(1H,d),12.7(1H,brs).

EIMS(m/z): 193(M⁺).

(c) The 3-(4-nitrophenyl)acrylic acid (99.7 mg) obtained in (b) aboveand the crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate(154.0 mg) obtained in the step (e) of Example 24 were dissolved in amixed solvent of dimethylformamide:dimethylsulfoxide=10:1 (2.75 ml). Inthe same manner as the method of (a) in Example 42, benzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(3-(4-nitrophenyl)acryloylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate(53 mg, 26.6%) was obtained.

TSPMS(m/z): 772(M⁺+1).

(d) In the same manner as the method of (b) in Example 42, the titlecompound:(S)-6-amino-2-((1-(3-(4-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:5) was obtained by using thebenzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(3-(4-nitrophenyl)acryloylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoateobtained in the above step (c) as a starting material.

¹H-NMR(D₂O): δ0.52-0.65(6H,m), 1.22-1.45(2H,m), 1.52-1.62(2H,m),1.64-1.72(2H,m), 1.81-1.98(1H,m), 2.45-2.59(2H,m), 2.68-2.84(2H,m),2.90(2H,t), 3.72-3.81(1H,m), 4.35-4.43(1H,m), 6.72(2H,d), 7.03(2H,d).

³¹P-NMR(D₂O): δ18.69(5/6P,s), 19.72(1/6P,s).

TSPMS(m/z): 430(M⁺+1).

Example 58(S)-6-Amino-2-((1-(3-(3-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 57, the title compound:(S)-6-amino-2-((1-(3-(3-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:4) was obtained by using3-nitrobenzaldehyde as the starting material.

¹H-NMR(D₂O): δ0.56-0.67(6H,m), 1.21-1.46(1H,m), 1.50-1.64(2H,m),1.64-1.73(2H,m), 1.80-2.30(1H,m), 2.45-2.62(2H,m), 2.70-2.84(2H,m),2.87-2.93(2H,m), 3.73-3.90(1H,m), 4.36-4.45(1H,m), 6.59-6.71(3H,m),7.08(1H,t).

³¹P-NMR(D₂O): δ18.65(4/5P,s), 19.72(1/5P,s).

TSPMS(m/z): 430(M⁺+1).

Example 59(S)-6-Amino-2-((2-methyl-1-(trifluoroacetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((2-methyl-1-(trifluoroacetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:6) was obtained by usingtrifluoroacetic anhydride instead of phenylacetyl chloride used in thestep (a) of Example 43.

¹H-NMR(D₂O): δ0.85(3H,d), 0.88(3H,d), 1.26-1.44(2H,m), 1.50-1.64(2H,m),1.64-1.76(2H,m), 2.03-2.15(1H,m), 2.88(2H,t), 3.87(1/7H,dd),3.89(6/7H,dd), 4.50-4.60(1H,m).

³¹P-NMR(D₂O): δ17.04(6/7P,s), 17.33(1/7P,s).

TSPMS(m/z): 379(M⁺+1).

Example 60(S)-6-Amino-2-((2-methyl-1-(3-phenyl-(2S)-(3-phenylpropanoylamino)propanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) L-phenylalanine (2 g) was dissolved in a mixed solvent ofdioxane:water=1:1 (20 ml), and the reaction system was cooled to 0° C.The solution was added with 1 N aqueous sodium hydroxide (12.1 ml), andfurther added dropwise with 1 N aqueous sodium hydroxide (12.1 ml) andhydrocinnamoyl chloride (1.98 ml) simultaneously over 25 minutes, andthen stirred at 0° C. for 2 hours. 1 N Hydrochloric acid was added tothe mixture to adjust the pH to 3, and the precipitated crystals werewashed with water and diethyl ether to obtain3-phenyl-(2S)-(3-phenylpropanoylamino)propanoic acid (2.9 g, 79.9%).

¹H-NMR(DMSO-d₆): δ2.36(2H,t), 2.72(2H,t), 2.84(1H,dd), 3.04(1H,dd),4.43(1H,ddd), 7.12-7.29(10H,m), 8.18(1H,d), 12.66(1H,brs).

TSPMS(m/z): 298(M⁺+1).

(b) In the same manner as the method of Example 46, the title compound:(S)-6-amino-2-((2-methyl-1-(3-phenyl-(2S)-(3-phenylpropanoylamino)propanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric isomer of 3:4) was obtained by using the3-phenyl-(2S)-(3-phenylpropanoylamino)propanoic acid obtained in theabove step (a) instead of 2,4-difluorobenzoic acid used in the step (a)of Example 46.

¹H-NMR(D₂O): δ0.65-0.84(6H,m), 1.21-1.41(2H,m), 1.49-1.61(2H,m),1.61-1.71(2H,m), 1.93-2.13(1H,m), 2.33-2.47(2H,m), 2.58-2.66(2H,m),2.67-2.77(1H,m), 2.82-2.90(2H,m), 2.98-3.14(1H,m), 3.78-3.89(1H,m),4.35-4.42(1H,m), 4.42-4.55(1H,m), 6.91-6.98(2H,m), 7.08-7.27(8H,m).

³¹P-NMR(D₂O): δ18.25(4/7P,s), 18.96(3/7P,s).

TSPMS(m/z): 562(M⁺+1).

Example 61(S)-6-Amino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) 4-Oxohexanoic acid (56.2 μl) was dissolved in methylene chloride(1.4 ml), and the solution was added with triethylamine (98.5 μl) andpivalic chloride (58.0 μl) and stirred under an argon atmosphere at roomtemperature for 15 minutes. The resulting mixture was added to amethylene chloride (1.4 ml) solution of the crude benzyl(S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanate(140.5 mg) obtained in the step (e) of Example 24, and the mixture wasfurther stirred at room temperature for 4 hours. Saturated aqueousammonium chloride was added to the mixture, and then the organicsubstances were extracted with ethyl acetate and the organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (15 g, hexane:acetone=3:1) to obtain benzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate(105.4 mg, 63.1%). This compound was subjected to the measurement ofmolecular weight and then used in the following reaction without furtherpurification.

TSPMS(m/z): 709(M⁺+1).

(b) In the same manner as the method of (b) in Example 42, the titlecompound:(S)-6-amino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using thebenzyl(S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoateobtained in the above step (a) as a starting material.

¹H-NMR(D₂O): δ0.76-0.86(6H,m), 1.23-1.50(2H,m), 1.51-1.77(4H,m),1.72(2H,q), 1.90-2.10(1H,m), 2.09(3H,s), 2.13-2.24(2H,m), 2.49(1H,t),2.50(1H,t), 2.89(1H,t), 2.90(1H,t), 3.78-3.87(1H,m), 4.35-4.45(1H,m).

³¹P-NMR(D₂O): δ18.56(1/2P,s), 19.63(1/2P,s).

TSPMS(m/z): 395(M⁺+1).

Example 62(S)-6-Amino-2-((1-((3R)-hydroxybutanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 42, the title compound:(S)-6-amino-2-((1-((3R)-hydroxybutanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using(3R)-benzyloxybutanoic acid, prepared by the method described in Helv.Chem. Acta., 155(1988), instead of N-benzyloxycarbonyl-L-phenylalaninein (a) of Example 42.

¹H-NMR(D₂O): δ0.77-0.87(6H,d), 1.12(3H,d), 1.25-1.45(2H,m),1.50-1.62(2H,m), 1.62-1.72(2H,m), 1.95-2.10(1H,m), 2.26-2.40(2H,m),2.90(2H,t), 3.85(1H,dd), 4.00-4.15(1H,m), 4.36-4.45(1H,m).

³¹P-NMR(D₂O): δ18.59(1/2P,s), 19.59(1/2P,s).

TSPMS(m/z): 369(M⁺+1).

Example 63(S)-6-Amino-2-((1-(3-methoxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

(a) 3-Methoxypropanoic acid (1.1 g) was dissolved in methylene chloride(11 ml), and the solution was added with thionyl chloride (2.51 g) andthen warmed to 40° C. and stirred for 2 hours. The reaction system wasconcentrated under reduced pressure without any treatment to obtaincrude 3-methoxypropionyl chloride. This compound was used in thefollowing reaction without further purification.

(b) In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((1-(3-methoxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using the3-methoxypropionyl chloride obtained in the above step (a) instead ofphenylacetyl chloride in (a) of Example 43.

¹H-NMR(D₂O): δ0.75-0.86(6H,m), 1.25-1.45(2H,m), 1.51-1.62(2H,m),1.62-1.72(2H,m), 1.92-2.11(1H,m), 2.36-2.52(2H,m), 2.89(2H,t),3.238(3/2H,s), 3.242(3/2H,s), 3.56-3.67(2H,m), 3.83(1/2H,t),3.87(1/2H,t), 4.35-4.45(1H,m).

³¹P-NMR(D₂O): δ18.57(1/2P,s), 19.61(1/2P,s).

TSPMS(m/z): 369(M⁺+1).

Example 64(S)-6-Amino-2-((2-methyl-1-(3,4,5-trimethoxybenzoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((2-methyl-1-(3,4,5-trimethoxybenzoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by using3,4,5-trimethoxybenzoyl chloride instead of phenylacetyl chloride usedin the step (a) of Example 43.

¹H-NMR(D₂O): δ0.85-0.93(6H,m), 1.17-1.36(2H,m), 1.39-1.54(2H,m),1.60-1.72(2H,m), 2.05-2.17(1H,m), 2.72(1H,t), 2.74(1H,t), 3.70(3H,s),3.79(6H,s), 4.07(1H,dt), 4.51-4.60(1H,m), 7.05(2H,d).

³¹P-NMR(D₂O): δ18.98(1/2P,s), 19.58(1/2P,s).

TSPMS(m/z): 477(M⁺+1).

Example 65(S)-6-Amino-2-((1-(3-carboxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 61, the title compound:(S)-6-amino-2-((1-(3-carboxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 1:1) was obtained by usingmonobenzyl succinate instead of 4-oxohexanoic acid used in the step (a)of Example 61.

¹H-NMR(D₂O): δ0.76-0.86(6H,m), 1.20-1.42(2H,m), 1.51-1.61(2H,m),1.61-1.70(2H,m), 1.93-2.10(1H,m), 2.36(2H,d), 2.39-2.56(2H,m),2.88(2H,t), 3.77-3.88(1H,m), 4.33-4.45(1H,m).

³¹P-NMR(D₂O): δ18.86(112P,s), 19.96(1/2P,s).

TSPMS(m/z): 383(M⁺+1).

Example 66(S)-6-Amino-2-((2-methyl-1-(pyridin-2-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 61, the title compound:(S)-6-amino-2-((2-methyl-1-(pyridin-2-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 4:5) was obtained by usingpicolinic acid instead of 4-oxohexanoic acid used in the step (a) ofExample 61.

¹H-NMR(D₂O): δ0.86-0.94(6H,m), 1.10-1.65(6H,m), 2.06-2.25(1H,m),2.71(8/9H,t), 2.76(10/9H,t), 4.05(1H,dt), 4.34-4.42(1H,brm),7.51(1H,brm), 7.87-7.95(2H,brm), 8.49-8.51(1H,brs).

³¹P-NMR(D₂O): δ18.20(5/9P,s), 18.94(4/9P,s).

TSPMS(m/z): 388(M⁺+1).

Example 67(S)-6-Amino-2-((2-methyl-1-(morpholine-4-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 43, the title compound:(S)-6-amino-2-((2-methyl-1-(morpholine-4-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid (a diastereoisomeric mixture of 3:4) was obtained by using4-morpholinecarbonyl chloride instead of phenylacetyl chloride used inthe step (a) of Example 43.

¹H-NMR(D₂O): δ0.73-0.85(6H,m), 1.24-1.46(2H,m), 1.49-1.71(4H,m),1.84-2.09(1H,m), 2.89(2H,dt), 3.25-3.39(4H,m), 3.59-3.65(4H,m),3.76(1H,dt), 4.33-4.43(1H,m).

³¹P-NMR(D₂O): δ19.85(4/7P,s), 20.76(3/7P,s).

TSPMS(m/z): 396(M⁺+1).

Example 684-((2-Methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid

(a) 4-Cyano-1-ethoxycarbonyl-4-hydroxypiperidine (304 mg) described inTetrahedron) 7625(1999) was dissolved in 50% sulfuric acid (3 ml) andthe solution was refluxed for 19 hours. The reaction mixture was dilutedwith water, and then roughly purified with Muromac AG50WX8 (MuromachiKagaku Kogyo Co., 20 cc, elution with aqueous NH₄) to obtain crude4-hydroxypiperidine-4-carboxylic acid. This crude4-hydroxypiperidine-4-carboxylic acid was subjected to the measurementof molecular weight and then used in the following reaction withoutfurther purification.

TSPMS(m/z): 146(M⁺+1).

(b) The crude 4-hydroxypiperidine-4-carboxylic acid obtained in theabove step (a) was dissolved in a mixed solvent of 1 N aqueous sodiumhydroxide (1.4 ml) and tetrahydrofuran (2 ml), and the solution wasadded with benzyl chloroformate (0.1 ml). The reaction mixture wasstirred at room temperature for 2 hours and 30 minutes, and thenacidified with hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated to obtain crude1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid. This crude1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid was subjectedto the measurement of molecular weight and then used in the followingreaction without further purification.

TSPMS(m/z): 280(M⁺+1).

(c) To a N,N-dimethylformamide solution (3 ml) of the crude1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid obtained inthe above step (b), potassium carbonate (121 mg) and benzyl bromide (0.1ml) were added, and the mixture was stirred at room temperature for 13hours. The organic substances were extracted with ethyl acetate, and theextract was washed with saturated brine, and then dried over anhydrousmagnesium sulfate. The solvent was evaporated, and then the residue waspurified by silica gel column chromatography (10 g, hexane:ethylacetate=2:1˜1:1) to obtain benzyl1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylate (110 mg, 19% (3steps)).

¹H-NMR(CDCl₃): δ1.5-1.7(2H,m), 1.9-2.1(2H,m), 3.1-3.3(2H,m),3.9-4.2(2H,m), 5.13(2H,brs), 5.21(2H,s), 7.3-7.4(10H,m).

TSP(m/z): (M⁺+1). (d) In the same manner as the method of Example 2, thetitle compound:4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid was obtained by using the benzyl1-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylate obtained in theabove step (c) instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the step (b) ofExample 2.

¹H-NMR(D₂O): δ0.65(3H,d), 0.66(3H,d), 1.9-2.13(3H,m), 2.15-2.3(2H,m),2.5-2.75(2H,m), 2.8-3.0(2H,m), 3.76(1H,dd), 7.18(1H,t), 7.23-7.35(4H,m).

TSPMS(m/z): 413(M⁺+1).

Example 691-Amidino-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid

(a) The 4-hydroxypiperidine-4-carboxylic acid (279 mg) obtained in thestep (a) of Example 68 and triethylamine (0.6 ml) were dissolved in amixed solvent of tetrahydrofuran (6 ml) and water (6 ml). The resultingsolution was added with 1-(N¹,N²-bisbenzyloxycarbonylamidino)pyrazole(728 mg) described in Tetrahedron Lett., 3389(1993) and stirred at roomtemperature for 17.5 hours. The reaction mixture was added withsaturated aqueous sodium hydrogencarbonate, washed with ethyl acetate,and then acidified with hydrochloric acid. The organic substances wereextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated to obtain1-(N¹,N²-bisbenzyloxycarbonylamidino)-4-hydroxypiperidine-4-carboxylicacid (404 mg, 46%).

¹H-NMR(CDCl₃): δ1.65(2H,d), 2.14(2H,dd), 3.41(2H,dd), 4.00(2H,d),5.13(4H,s), 7.2-7.4(10H,m), 7.8-8.3(1H,brs).

TSPMS(m/z): 456(M⁺+1).

(b) To a N,N-dimethylformamide (0.5 ml) solution of the1-(N¹,N²-bisbenzyloxycarbonylamidino)-4-hydroxypiperidine-4-carboxylicacid (72 mg) obtained in the above step (a), potassium carbonate (27 mg)and benzyl bromide (20 μl) were added. The reaction mixture was stirredat room temperature for 14 hours, and then extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue waspurified by silica gel column chromatography (15 g, hexane:ethylacetate=1:1) to obtain benzyl1-(N¹,N²-bisbenzyloxycarbonylamidino)-4-hydroxypiperidine-4-carboxylate(64 mg, 74%).

¹H-NMR(DMSO-d₆): δ1.68(2H,s), 1.88(2H,dd), 3.20(2H,dd), 3.7-3.9(2H,m),4.9-5.1(2H,m), 5.15(2H,s), 7.3-7.5(15H,m).

TSPMS(m/z): 546(M⁺+1).

(c) In the same manner as the method of Example 2, the title compound:1-amidino-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid was obtained by using the benzyl1-(N¹,N²-bisbenzyloxycarbonylamidino)-4-hydroxypiperidine-4-carboxylateobtained in the above step (b) instead of benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate in (b) of Example 2.

¹H-NMR(CD₃OD): δ0.85-1.0(6H,m), 1.95-2.3(5H,m), 3.4-3.8(8H,m),3.9-4.0(1H,m), 7.1-7.3(5H,m).

TSPMS(m/z): 455(M⁺+1).

Example 701-(2-Aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid

(a) The 4-hydroxypiperidine-4-carboxylic acid (118 mg) obtained in thestep (a) of Example 68 was dissolved in 1 N hydrochloric acid/ethanol (5ml) solution, and the resulting solution was stirred at room temperaturefor 17 hours and then under reflux for 6 hours. The reaction mixture wasconcentrated to obtain crude ethyl 4-hydroxypiperidine-4-carboxylate.This crude ethyl 4-hydroxypiperidine-4-carboxylate was used in thefollowing reaction without purification.

(b) To a N,N-dimethylformamide (3 ml) solution of the crude ethyl4-hydroxy-piperidine-4-carboxylate obtained in the above step (a),(2-benzyloxycarbonylamino)ethyl p-toluenesulfonate (311 mg), obtainedfrom aminoethanol in a conventional manner, and potassium carbonate (245mg) were added, and the mixture was stirred at room temperature for 14hours and at 50° C. for hours. The organic substances were extractedwith ethyl acetate, and the extract was washed with saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography and then with LH-20 (Sephadex) to obtain ethyl1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylate (118mg, 42% (2 steps)).

¹H-NMR(CDCl₃): δ1.29(3H,t), 1.61(2H,d), 2.05(2H,dd), 2.39(2H,dd),2.50(2H,t), 2.69(2H,d), 3.31(2H,d), 4.22(2H,q), 5.10(2H,s),5.44(1H,brs), 7.3-7.4(5H,m).

TSPMS(m/z): 351(M⁺+1).

(c) The ethyl1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylate (118mg) obtained in the above step (b) was dissolved in tetrahydrofuran (0.5ml), and the solution was added with 1 N aqueous sodium hydroxide (0.35ml) and stirred at room temperature for 4 hours. Then the reactionmixture was purified by using HP-20 (Diaion, 80 cc, methanol:water=1:1)to obtain sodium salt of1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylic acid(91 mg).

¹H-NMR(D₂O): δ1.52(2H,d), 1.94(2H,dd), 2.38(2H,dd), 2.53(2H,t),2.78(2H,d), 3.23(2H,d), 5.01(2H,s), 7.2-7.4(5H,m).

TSPMS(m/z): 323(M⁺+1).

(d) To a N,N-dimethylformamide (2.5 ml) solution of the sodium salt of1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylic acid(91 mg) obtained in the above step (c), sodium carbonate (27 mg) andbenzyl bromide (35 μl) were added, and the mixture was stirred at roomtemperature for 25 hours. The organic substances were extracted withethyl acetate, and the extract was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography (8 g, methylenechloride:methanol=10:1) and then by using LH-20 (Sephadex, 80 cc,methylene chloride:methanol=1:1) to obtain benzyl1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylate (66mg, 61%).

¹H-NMR(CDCl₃): δ1.62(2H,d), 2.07(2H,dd), 2.38(2H,dd), 2.48(2H,t),2.68(2H,d), 3.29(2H,t), 5.09(2H,s), 5.20(2H,s), 5.38(1H,brs),7.2-7.4(10H,m).

TSPMS(m/z): 413(M⁺+1).

(e) 1-Amino-2-methylpropylphosphonic acid (2.7 g) described in Synthesis370(1988) was dissolved in water (27 ml), and the solution was addedwith 5 N aqueous sodium hydroxide (10.5 ml) and 3-phenylpropanoylchloride (2.6 ml) and stirred at room temperature for 16 hours. Thereaction mixture was washed with diethyl ether and acidified withhydrochloric acid. The organic substances were extracted with ethylacetate, and the extract was washed with saturated brine to obtain2-methyl-1-(3-phenylpropanoylamino)propylphosphonic acid (554 mg, 11%).

¹H-NMR(CDCl₃): δ0.82(3H,d), 0.84(3H,d), 2.0-2.2(1H,m), 2.5-2.7(2H,m),2.9-3.0(2H,m), 4.1-4.2(1H,m), 6.70(1H,d), 7.1-7.3(5H,m).

TSPMS(m/z): 286(M⁺+1).

(f) To a methylene chloride (0.4 ml) solution of the benzyl1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylate (109mg) obtained in the above step (d), the2-methyl-1-(3-phenylpropanoylamino)propylphosphonic acid (96 mg)obtained in the above step (e) andN-(dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (86 mg) wereadded, and the resulting mixture was stirred at room temperature for25.5 hours. The reaction mixture was purified by using LH-20 (Sephadex,300 cc, methylene chloride:methanol=1:1) to obtain benzyl1-(2-benzyloxycarbonylaminoethyl)-4-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylate(56 mg, 26%).

¹H-NMR(CDCl₃): δ0.79(6H,d), 2.0-2.5(5H,m), 2.8-3.5(12H,m),3.9-4.1(1H,m), 5.05(2H,s), 5.07(2H,s), 7.1-7.3(15H,m).

TSPMS(m/z): 680(M⁺+1).

(g) The benzyl1-(2-benzyloxycarbonylaminoethyl)-4-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylate(56 mg) obtained in the above step (f) was dissolved in a mixed solventof dioxane (1.5 ml) and water (0.5 ml), and then the solution was addedwith palladium hydroxide (13 mg). The mixture was stirred under ahydrogen atmosphere at room temperature for 3 hours. The reactionmixture was filtered with celite, and then the solvent was evaporated.The residue was purified with HP-20 (Diaion, 40 cc, methanol:water=1:1to acetone:water=1:4)) to obtain the titlecompound:1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylicacid (32 mg, 84%).

¹H-NMR(D₂O): δ0.61(6H,d), 1.8-2.15(3H,m), 2.15-2.4(2H,m), 2.5-2.7(2H,m),2.75-2.95(2H,m), 3.2-3.5(8H,m), 3.70(1H,dd), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ18.7(1P,s).

FABMS(m/z): 456(M⁺+1).

Example 71(R)-6-Amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 2, the title compound:(R)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using (1R)-amino-2-methylphosphinic acid instead ofamino-2-methylphosphinic acid used in the step (a) of Example 2, andusing benzyl (R)-6-benzyloxycarbonylamino-2-hydroxyhexanoate instead ofbenzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate used in the abovestep (b) of Example 2.

¹H-NMR(D₂O): δ0.60(6H,d), 1.2-1.5(2H,m), 1.5-1.8(4H,m), 1.8-2.0(1H,m),2.5-2.7(2H,m), 2.8-3.0(4H,m), 3.79(1H,dd), 4.41(1H,dt), 7.1-7.4(5H,m).

³¹P-NMR(D₂O): δ18.6(1P,s).

FABMS(m/Z): 415(M⁺+1).

Example 727-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylheptanoicacid

In the same manner as the method of Example 22, the title compound:7-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylheptanoicacid (a diastereoisomeric mixture of 1:3) was obtained by using5-aminopentanol instead of 4-amino-1-butanol used in the step (a) ofExample 22.

¹H-NMR(D₂O): δ0.6-0.7(6H,m), 1.1-1.7(1OH,m), 1.9-2.1(1H,m),2.4-2.5(1H,m), 2.5-2.7(2H,m), 2.7-2.9(4H,m), 3.6-3.7(1H,m),7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ38.3(1/4P,s), 37.9(3/4P,s).

TSPMS(m/z): 427(M⁺+1).

Example 73(S)-6-Amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid

In the same manner as the method of Example 70, the title compound:(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoicacid was obtained by using benzyl(S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate instead of benzyl1-(2-benzyloxycarbonylaminoethyl)-4-hydroxypiperidine-4-carboxylate usedin the step (f) of Example 70. The spectrum data of the resultingcompound showed similar values to those of the compound obtained inExample 2.

¹H-NMR(D₂O): δ0.56(1.5H,d), 0.59(3H,m), 0.66(1.5H,d), 1.2-1.5(2H,m),1.6-1.8(4H,m), 1.8-2.0(1H,m), 2.5-2.7(2H,m), 2.8-3.0(4H,m),3.7-3.9(1H,m), 4.3-4.5(1H,m), 7.1-7.3(5H,m).

³¹P-NMR(D₂O): δ18.7(0.5P,s), 19.7(0.5P,s).

TSPMS(m/z): 415(M⁺+1).

Chemical structures of the title compounds according to Examples 1 to 73are as follows:

Ex- am- ple No. Chemical structure 1

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Pharmacological Test Example: Inhibitory Activity AgainstCarboxypeptidase B

Inhibitory activity of the compounds of the present invention againstcarboxypeptidase B was measured as follows according to the methoddescribed in Thromb. Haemost. 371(1998).

(a) Partial Purification of Carboxypeptidase B Precursor (pro-CPB) fromHuman Plasma

Human plasma collected over citric acid was added with 80 mM bariumchloride and treated at 4° C. for 30 minutes. The supernatant obtainedby centrifugation at 10,000 rpm for 20 minutes was dialyzed against 20mM HEPES buffer containing 0.15 M sodium chloride (pH 7.4). Furthermore,protein in the fractions obtained with 30% to 80% ammonium sulfate werepartially purified by chromatography using a Q-Sepharose column (elutionwith 50 mM tris-HCl buffer (pH 7.4) gradually containing sodium chlorideto 0.5 M).

(b) Activation of pro-CPB

pro-CPB (20 μl) was added with 20 μl of a thrombomodulin solution(Thrombomodulin derived from rabbit lung, American Diagnostia Inc.,Product No. #237, dissolved at concentration of 300 ng/ml in buffer A as50 mM tris-HCl buffer (pH 7.4) supplemented with 0.1% Lubrol, 0.1% BSAand 0.15 M sodium chloride), and treated at 25° C. for 3 minutes. Then,the mixture was added with 20 μl of thrombin (Thrombin derived fromhuman plasma, Sigma, Product No. T8885, dissolved at concentration of 3u/ml in buffer B as 50 mM Tris-HCl buffer (pH 7.4) supplemented with0.1% BSA, 0.15 M NaCl and 10 mM calcium chloride) and further treated at25° C. for 30 minutes for activation(*1).

(c) Measurement of CPB Inhibitory Activity

By using a microplate, 4 μl of the sample was added with a mixedsolution of 41 μl of buffer C (0.1 M tris-HCl buffer (pH 7.6)) and 25 μlof a substrate solution (Hip-Arg, Sigma, H2508, dissolved in buffer C atconcentration of 4 mM.), and further added with 10 μl of the activatedCPB solution (*1), and then the mixture was well mixed and allowed toreact at 25° C. for 60 minutes. Then, 100 μl of 0.2 M PIPES buffer (pH7.5) containing 12.5% Tween was added to the mixture to stop thereaction. After 5 minutes, the mixture was added with 100 μl of acoloring solution (2-methoxyethanol containing 1% cyanuryl chloride) andallowed to stand at room temperature for 15 minutes, and then absorbancewas measured at 405 nm by using a microplate reader (Bio Rad Model3550).

Inhibitory activity against carboxypeptidase B was calculated by usingthe following equation as an inhibitory rate, wherein A representsabsorbance in the absence of a tested substance; B represents absorbancein the presence of a tested substance (500 nM); A′ and B′ represent theaforementioned absorbances obtained by using non-activated enzymewithout and with the tested substance, respectively.

Inhibitory rate (%)=[1−{(B-B′)/(A-A′)}]×100

The results of the carboxypeptidase B inhibitory rates are shown inTable 1, which were calculated by using the above equation and theresults of the measurements in the above experiments for the compoundsof the present invention.

TABLE 1 Carboxypeptidase B inhibitory rates Compound in Examples bytested substance at 500 nM 1 30 2 >90 3 >90 4 >90 5 30 6 >90 8 >90 9 >9010 >90 12 >90 14 >90 16 >90 19 >90 20 >90 23 50 24 >90 25 80 34 4035 >90 37 70 39 >90 40 30 41 >90

Toxicity Test Example by Single Administration

The compound of Example 19 of the present invention was dissolved insaline intravenously administered to 6 individuals of ICR male mice of 5weeks old. At the dose of 1 g/kg of the compound of Example 19, no deathof the mice or severe toxicity was observed.

Formulation Example 1

The compound of Example 19 according to the present invention (25 g) wasdissolved in water for injection (450 ml), and the solution was addedwith sodium hydroxide (1.6 g), and adjusted to 500 ml with water forinjection. A filtrate was obtained by treating the solution with amembrane for sterile filtration, and aliquots of 1.0 ml were filled invials. Lyophilization in a conventional manner gave lyophilized vialpreparations containing the compound of Example 19 (50 mg). Thepreparation obtained can be intravenously administered after thepreparation is dissolved in saline, or administered by intravenous dripinfusion after the resulting solution is added in saline (100 ml) andthe like.

Formulation Example 2

The compound of Example 19 according to the present invention (5 g) wasdissolved in water for injection (450 ml), and the solution was addedwith disodium hydrogenphosphate (2.6 g) and then adjusted to 500 ml withwater for injection. A filtrate was obtained by treating the solutionwith a membrane for sterile filtration, and aliquots of 1.0 ml werefilled in vials. Lyophilization in a conventional manner gavelyophilized vial preparations containing the compound of Example 19 (10mg). The preparation obtained can be intravenously administered afterthe preparation is dissolved in saline, or administered by intravenousdrip infusion after the resulting solution is added in saline (100 ml)and the like.

What is claimed is:
 1. A compound represented by the following formula(I) or a pharmacologically acceptable salt thereof, or a hydrate thereofor a solvate thereof:

wherein R¹ represents phenylethyl group; R² represents isopropyl group;R³ represents hydrogen atom; X represents —CH₂— or —O—; A represents agroup of the following formula (II):

in which R⁷ and R⁸ represent hydrogen atoms; R⁹ and R¹⁰ representhydrogen atoms; m represents 5; and —(C)_(m)— represents a saturatedcarbon chain, and, E represents hydrogen atom.
 2. The compound or thepharmacologically acceptable salt thereof, or the hydrate thereof or thesolvate thereof according to claim 1, which is(S)-7-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxy-phosphinoyl)oxy)heptanoicacid, or7-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)-methylheptanoicacid.
 3. A medicament composition which comprises as an activeingredient a substance selected from the group consisting of thecompound and the pharmacologically acceptable salt thereof, and thehydrate thereof and the solvate thereof according to claim
 1. 4. Amedicament composition which comprises as an active ingredient asubstance selected from the group consisting of the compound and thepharmacologically acceptable salt thereof, and the hydrate thereof andthe solvate thereof according to claim
 2. 5. A medicament in the form ofa pharmaceutical composition which comprises a substance selected fromthe group consisting of the compound and the pharmacologicallyacceptable salt thereof, and the hydrate and the solvate thereofaccording to claim 1 together with a pharmacologically acceptablecarrier.
 6. A medicament in the form of a pharmaceutical compositionwhich comprises a substance selected from the group consisting of thecompound and the pharmacologically acceptable salt thereof, and thehydrate and the solvate thereof according to claim 2 together with apharmacologically acceptable carrier.
 7. The medicament compositionaccording to claim 3 which is used for therapeutic and/or preventivetreatment of a thrombotic disease.
 8. The medicament compositionaccording to claim 4 which is used for therapeutic and/or preventivetreatment of a thrombotic disease.
 9. The medicament according to claim5 which is used for therapeutic and/or preventive treatment of athrombotic disease.
 10. The medicament according to claim 6 which isused for therapeutic and/or preventive treatment of a thromboticdisease.
 11. An inhibitor composition against carboxypeptidase B whichcomprises a substance selected from the group consisting of the compoundand the pharmacologically acceptable salt thereof, and the hydratethereof and the solvate thereof according to claim
 1. 12. An inhibitorcomposition against carboxypeptidase B which comprises a substanceselected from the group consisting of the compound and thepharmacologically acceptable salt thereof, and the hydrate thereof andthe solvate thereof according to claim
 2. 13. A method for therapeutictreatment of a thrombotic disease which comprises administering to amammal a therapeutically effective amount of a substance selected fromthe group consisting of the compound and the pharmacologicallyacceptable salt thereof, and the hydrate thereof and the solvate thereofaccording to claim
 1. 14. A method for therapeutic treatment of athrombotic disease which comprises administering to a mammal atherapeutically effective amount of a substance selected from the groupconsisting of the compound and the pharmacologically acceptable saltthereof, and the hydrate thereof and the solvate thereof according toclaim
 2. 15. A method for preventive treatment of a thrombotic diseasewhich comprises administering to a mammal a preventively effectiveamount of a substance selected from the group consisting of the compoundand the pharmacologically acceptable salt thereof, and the hydratethereof and the solvate thereof according to claim
 1. 16. A method forpreventive treatment of a thrombotic disease which comprisesadministering to a mammal a preventively effective amount of a substanceselected from the group consisting of the compound and thepharmacologically acceptable salt thereof, and the hydrate thereof andthe solvate thereof according to claim
 2. 17. The method according toclaim 13, wherein the mammal is a human.
 18. The method according toclaim 14, wherein the mammal is a human.
 19. The method according toclaim 15, wherein the mammal is a human.
 20. The method according toclaim 16, wherein the mammal is a human.